Methods of reducing the risk of a cardiovascular event in a subject on statin therapy

ABSTRACT

In various embodiments, the present invention provides methods of reducing the risk of a cardiovascular event in a subject on statin therapy and, in particular, a method of reducing the risk of a cardiovascular event in a subject on statin therapy having a fasting baseline triglyceride level of about 135 mg/dL to about 500 mg/dL, and administering to the subject a pharmaceutical composition comprising about 1 g to about 4 g of eicosapentaenoic acid ethyl ester or a derivative thereof.

PRIORITY CLAIM

This application is a continuation of U.S. patent application Ser. No.16/156,879 filed Oct. 10, 2018, which is a continuation of U.S. patentapplication Ser. No. 16/005,852 filed Jun. 12, 2018, which is acontinuation of U.S. patent application Ser. No. 15/886,422 filed Feb.1, 2018, which is a continuation application of U.S. patent applicationSer. No. 15/607,084 filed May 26, 2017 (now U.S. Pat. No. 9,918,955),which is a continuation of U.S. patent application Ser. No. 15/427,238filed Feb. 8, 2017 (now U.S. Pat. No. 9,693,986), which is acontinuation application of U.S. patent application Ser. No. 15/333,991filed Oct. 25, 2016 (now U.S. Pat. No. 9,610,272), which is acontinuation of U.S. patent application Ser. No. 14/411,815, filed Dec.29, 2014 (now U.S. Pat. No. 9,603,826), which is a 371 national stageapplication of PCT/US2013/048559 filed Jun. 28, 2013, and which claimspriority to U.S. provisional patent application Ser. No. 61/666,447,filed Jun. 29, 2012, the entire contents of which are incorporatedherein by reference.

BACKGROUND

Cardiovascular disease is one of the leading causes of death in theUnited States and most European countries. It is estimated that over 70million people in the United States alone suffer from a cardiovasculardisease or disorder including but not limited to high blood pressure,coronary heart disease, dyslipidemia, congestive heart failure andstroke.

Lovaza®, a lipid regulating agent, is indicated as an adjunct to diet toreduce triglyceride levels in adult patients with very high triglyceridelevels. Unfortunately, Lovaza® can significantly increase LDL-C and/ornon-HDL-C levels in some patients. A need exists for improved treatmentsfor cardiovascular diseases and disorders.

SUMMARY

In various embodiments, the present invention provides methods ofreducing the risk of a cardiovascular event in a subject on statintherapy. In one embodiment, the method comprises administering to thesubject a pharmaceutical composition comprising about 1 g to about 4 gof eicosapentaenoic acid ethyl ester or a derivative thereof. In anotherembodiment, the subject has a fasting baseline triglyceride level ofabout 135 mg/dL to about 500 mg/dL. In another embodiment, thecomposition contains not more than 10%, by weight, docosahexaenoic acidor derivative thereof, substantially no docosahexaenoic acid orderivative thereof, or no docosahexaenoic acid or derivative thereof. Inanother embodiment, eicosapentaenoic acid ethyl ester comprises at least96%, by weight, of all fatty acids present in the composition; thecomposition contains not more than 4%, by weight, of total fatty acidsother than eicosapentaenoic acid ethyl ester; and/or the compositioncontains about 0.1% to about 0.6% of at least one fatty acid other thaneicosapentaenoic acid ethyl ester and docosahexaenoic acid.

In another embodiment, the invention provides a method of treatinghypertriglyceridemia comprising administering a composition as describedherein to a subject in need thereof one to about four times per day.

These and other embodiments of the present invention will be disclosedin further detail herein below.

DETAILED DESCRIPTION

While the present invention is capable of being embodied in variousforms, the description below of several embodiments is made with theunderstanding that the present disclosure is to be considered as anexemplification of the invention, and is not intended to limit theinvention to the specific embodiments illustrated. Headings are providedfor convenience only and are not to be construed to limit the inventionin any manner. Embodiments illustrated under any heading may be combinedwith embodiments illustrated under any other heading.

The use of numerical values in the various quantitative values specifiedin this application, unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within thestated ranges were both preceded by the word “about.” Also, thedisclosure of ranges is intended as a continuous range including everyvalue between the minimum and maximum values recited as well as anyranges that can be formed by such values. Also disclosed herein are anyand all ratios (and ranges of any such ratios) that can be formed bydividing a disclosed numeric value into any other disclosed numericvalue. Accordingly, the skilled person will appreciate that many suchratios, ranges, and ranges of ratios can be unambiguously derived fromthe numerical values presented herein and in all instances such ratios,ranges, and ranges of ratios represent various embodiments of thepresent invention.

Compositions

In one embodiment, a composition of the invention is administered to asubject in an amount sufficient to provide a daily dose ofeicosapentaenoic acid of about 1 mg to about 10,000 mg, 25 about 5000mg, about 50 to about 3000 mg, about 75 mg to about 2500 mg, or about100 mg to about 1000 mg, for example about 75 mg, about 100 mg, about125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg,about 1025 mg, about 1050 mg, about 1075 mg, about 1200 mg, about 1225mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg,about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg,about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, about 1925mg, about 1950 mg, about 1975 mg, about 2000 mg, about 2025 mg, about2050 mg, about 2075 mg, about 2100 mg, about 2125 mg, about 2150 mg,about 2175 mg, about 2200 mg, about 2225 mg, about 2250 mg, about 2275mg, about 2300 mg, about 2325 mg, about 2350 mg, about 2375 mg, about2400 mg, about 2425 mg, about 2450 mg, about 2475 mg, about 2500 mg,about 2525 mg, about 2550 mg, about 2575 mg, about 2600 mg, about 2625mg, about 2650 mg, about 2675 mg, about 2700 mg, about 2725 mg, about2750 mg, about 2775 mg, about 2800 mg, about 2825 mg, about 2850 mg,about 2875 mg, about 2900 mg, about 2925 mg, about 2950 mg, about 2975mg, about 3000 mg, about 3025 mg, about 3050 mg, about 3075 mg, about3100 mg, about 3125 mg, about 3150 mg, about 3175 mg, about 3200 mg,about 3225 mg, about 3250 mg, about 3275 mg, about 3300 mg, about 3325mg, about 3350 mg, about 3375 mg, about 3400 mg, about 3425 mg, about3450 mg, about 3475 mg, about 3500 mg, about 3525 mg, about 3550 mg,about 3575 mg, about 3600 mg, about 3625 mg, about 3650 mg, about 3675mg, about 3700 mg, about 3725 mg, about 3750 mg, about 3775 mg, about3800 mg, about 3825 mg, about 3850 mg, about 3875 mg, about 3900 mg,about 3925 mg, about 3950 mg, about 3975 mg, about 4000 mg, about 4025mg, about 4050 mg, about 4075 mg, about 4100 mg, about 4125 mg, about4150 mg, about 4175 mg, about 4200 mg, about 4225 mg, about 4250 mg,about 4275 mg, about 4300 mg, about 4325 mg, about 4350 mg, about 4375mg, about 4400 mg, about 4425 mg, about 4450 mg, about 4475 mg, about4500 mg, about 4525 mg, about 4550 mg, about 4575 mg, about 4600 mg,about 4625 mg, about 4650 mg, about 4675 mg, about 4700 mg, about 4725mg, about 4750 mg, about 4775 mg, about 4800 mg, about 4825 mg, about4850 mg, about 4875 mg, about 4900 mg, about 4925 mg, about 4950 mg,about 4975 mg, about 5000 mg, about 5025 mg, about 5050 mg, about 5075mg, about 5100 mg, about 5125 mg, about 5150 mg, about 5175 mg, about5200 mg, about 5225 mg, about 5250 mg, about 5275 mg, about 5300 mg,about 5325 mg, about 5350 mg, about 5375 mg, about 5400 mg, about 5425mg, about 5450 mg, about 5475 mg, about 5500 mg, about 5525 mg, about5550 mg, about 5575 mg, about 5600 mg, about 5625 mg, about 5650 mg,about 5675 mg, about 5700 mg, about 5725 mg, about 5750 mg, about 5775mg, about 5800 mg, about 5825 mg, about 5850 mg, about 5875 mg, about5900 mg, about 5925 mg, about 5950 mg, about 5975 mg, about 6000 mg,about 6025 mg, about 6050 mg, about 6075 mg, about 6100 mg, about 6125mg, about 6150 mg, about 6175 mg, about 6200 mg, about 6225 mg, about6250 mg, about 6275 mg, about 6300 mg, about 6325 mg, about 6350 mg,about 6375 mg, about 6400 mg, about 6425 mg, about 6450 mg, about 6475mg, about 6500 mg, about 6525 mg, about 6550 mg, about 6575 mg, about6600 mg, about 6625 mg, about 6650 mg, about 6675 mg, about 6700 mg,about 6725 mg, about 6750 mg, about 6775 mg, about 6800 mg, about 6825mg, about 6850 mg, about 6875 mg, about 6900 mg, about 6925 mg, about6950 mg, about 6975 mg, about 7000 mg, about 7025 mg, about 7050 mg,about 7075 mg, about 7100 mg, about 7125 mg, about 7150 mg, about 7175mg, about 7200 mg, about 7225 mg, about 7250 mg, about 7275 mg, about7300 mg, about 7325 mg, about 7350 mg, about 7375 mg, about 7400 mg,about 7425 mg, about 7450 mg, about 7475 mg, about 7500 mg, about 7525mg, about 7550 mg, about 7575 mg, about 7600 mg, about 7625 mg, about7650 mg, about 7675 mg, about 7700 mg, about 7725 mg, about 7750 mg,about 7775 mg, about 7800 mg, about 7825 mg, about 7850 mg, about 7875mg, about 7900 mg, about 7925 mg, about 7950 mg, about 7975 mg, about8000 mg, about 8025 mg, about 8050 mg, about 8075 mg, about 8100 mg,about 8125 mg, about 8150 mg, about 8175 mg, about 8200 mg, about 8225mg, about 8250 mg, about 8275 mg, about 8300 mg, about 8325 mg, about8350 mg, about 8375 mg, about 8400 mg, about 8425 mg, about 8450 mg,about 8475 mg, about 8500 mg, about 8525 mg, about 8550 mg, about 8575mg, about 8600 mg, about 8625 mg, about 8650 mg, about 8675 mg, about8700 mg, about 8725 mg, about 8750 mg, about 8775 mg, about 8800 mg,about 8825 mg, about 8850 mg, about 8875 mg, about 8900 mg, about 8925mg, about 8950 mg, about 8975 mg, about 9000 mg, about 9025 mg, about9050 mg, about 9075 mg, about 9100 mg, about 9125 mg, about 9150 mg,about 9175 mg, about 9200 mg, about 9225 mg, about 9250 mg, about 9275mg, about 9300 mg, about 9325 mg, about 9350 mg, about 9375 mg, about9400 mg, about 9425 mg, about 9450 mg, about 9475 mg, about 9500 mg,about 9525 mg, about 9550 mg, about 9575 mg, about 9600 mg, about 9625mg, about 9650 mg, about 9675 mg, about 9700 mg, about 9725 mg, about9750 mg, about 9775 mg, about 9800 mg, about 9825 mg, about 9850 mg,about 9875 mg, about 9900 mg, about 9925 mg, about 9950 mg, about 9975mg, or about 10,000 mg.

In one embodiment, a composition for use in methods of the inventioncomprises eicosapentaenoic acid, or a pharmaceutically acceptable ester,derivative, conjugate or salt thereof, or mixtures of any of theforegoing, collectively referred to herein as “EPA.” The term“pharmaceutically acceptable” in the present context means that thesubstance in question does not produce unacceptable toxicity to thesubject or interaction with other components of the composition.

In another embodiment, the EPA comprises an eicosapentaenoic acid ester.In another embodiment, the EPA comprises a C₁-C₅ alkyl ester ofeicosapentaenoic acid. In another embodiment, the EPA compriseseicosapentaenoic acid ethyl ester, eicosapentaenoic acid methyl ester,eicosapentaenoic acid propyl ester, or eicosapentaenoic acid butylester.

In another embodiment, the EPA is in the form of ethyl-EPA, lithium EPA,mono-, di- or triglyceride EPA or any other ester or salt of EPA, or thefree acid form of EPA. The EPA may also be in the form of a2-substituted derivative or other derivative which slows down its rateof oxidation but does not otherwise change its biological action to anysubstantial degree.

In another embodiment, EPA is present in a composition useful inaccordance with methods of the invention in an amount of about 50 mg toabout 5000 mg, about 75 mg to about 2500 mg, or about 100 mg to about1000 mg, for example about 75 mg, about 100 mg, about 125 mg, about 150mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1025 mg, about1050 mg, about 1075 mg, about 1200 mg, about 1225 mg, about 1250 mg,about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg,about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about1850 mg, about 1875 mg, about 1900 mg, about 1925 mg, about 1950 mg,about 1975 mg, about 2000 mg, about 2025 mg, about 2050 mg, about 2075mg, about 2100 mg, about 2125 mg, about 2150 mg, about 2175 mg, about2200 mg, about 2225 mg, about 2250 mg, about 2275 mg, about 2300 mg,about 2325 mg, about 2350 mg, about 2375 mg, about 2400 mg, about 2425mg, about 2450 mg, about 2475 mg, about 2500 mg, about 2525 mg, about2550 mg, about 2575 mg, about 2600 mg, about 2625 mg, about 2650 mg,about 2675 mg, about 2700 mg, about 2725 mg, about 2750 mg, about 2775mg, about 2800 mg, about 2825 mg, about 2850 mg, about 2875 mg, about2900 mg, about 2925 mg, about 2950 mg, about 2975 mg, about 3000 mg,about 3025 mg, about 3050 mg, about 3075 mg, about 3100 mg, about 3125mg, about 3150 mg, about 3175 mg, about 3200 mg, about 3225 mg, about3250 mg, about 3275 mg, about 3300 mg, about 3325 mg, about 3350 mg,about 3375 mg, about 3400 mg, about 3425 mg, about 3450 mg, about 3475mg, about 3500 mg, about 3525 mg, about 3550 mg, about 3575 mg, about3600 mg, about 3625 mg, about 3650 mg, about 3675 mg, about 3700 mg,about 3725 mg, about 3750 mg, about 3775 mg, about 3800 mg, about 3825mg, about 3850 mg, about 3875 mg, about 3900 mg, about 3925 mg, about3950 mg, about 3975 mg, about 4000 mg, about 4025 mg, about 4050 mg,about 4075 mg, about 4100 mg, about 4125 mg, about 4150 mg, about 4175mg, about 4200 mg, about 4225 mg, about 4250 mg, about 4275 mg, about4300 mg, about 4325 mg, about 4350 mg, about 4375 mg, about 4400 mg,about 4425 mg, about 4450 mg, about 4475 mg, about 4500 mg, about 4525mg, about 4550 mg, about 4575 mg, about 4600 mg, about 4625 mg, about4650 mg, about 4675 mg, about 4700 mg, about 4725 mg, about 4750 mg,about 4775 mg, about 4800 mg, about 4825 mg, about 4850 mg, about 4875mg, about 4900 mg, about 4925 mg, about 4950 mg, about 4975 mg, or about5000 mg.

In another embodiment, a composition useful in accordance with theinvention contains not more than about 10%, not more than about 9%, notmore than about 8%, not more than about 7%, not more than about 6%, notmore than about 5%, not more than about 4%, not more than about 3%, notmore than about 2%, not more than about 1%, or not more than about 0.5%,by weight, docosahexaenoic acid (DHA), if any. In another embodiment, acomposition of the invention contains substantially no docosahexaenoicacid. In still another embodiment, a composition useful in the presentinvention contains no docosahexaenoic acid and/or derivative thereof.

In another embodiment, EPA comprises at least 70%, at least 80%, atleast 90%, at least 95%, at least 96%, at least 97%, at least 98%, atleast 99%, or 100%, by weight, of all fatty acids present in acomposition that is useful in methods of the present invention.

In some embodiments, the composition comprises at least 96% by weight ofeicosapentaenoic acid ethyl ester and less than about 2% by weight of apreservative. In some embodiments, the preservative is a tocopherol suchas all-racemic α-tocopherol.

In another embodiment, a composition useful in accordance with methodsof the invention contains less than 10%, less than 9%, less than 8%,less than 7%, less than 6%, less than 5%, less than 4%, less than 3%,less than 2%, less than 1%, less than 0.5% or less than 0.25%, by weightof the total composition or by weight of the total fatty acid content,of any fatty acid other than EPA. Illustrative examples of a “fatty acidother than EPA” include linolenic acid (LA), arachidonic acid (AA),docosahexaenoic acid (DHA), alpha-linolenic acid (ALA), stearadonic acid(STA), eicosatrienoic acid (ETA) and/or docosapentaenoic acid (DPA). Inanother embodiment, a composition useful in accordance with methods ofthe invention contains about 0.1% to about 4%, about 0.5% to about 3%,or about 1% to about 2%, by weight, of total fatty acids other than EPAand/or DHA.

In another embodiment, a composition useful in accordance with theinvention has one or more of the following features: (a)eicosapentaenoic acid ethyl ester represents at least about 96%, atleast about 97%, or at least about 98%, by weight, of all fatty acidspresent in the composition; (b) the composition contains not more thanabout 4%, not more than about 3%, or not more than about 2%, by weight,of total fatty acids other than eicosapentaenoic acid ethyl ester; (c)the composition contains not more than about 0.6%, not more than about0.5%, or not more than about 0.4% of any individual fatty acid otherthan eicosapentaenoic acid ethyl ester; (d) the composition has arefractive index (20° C.) of about 1 to about 2, about 1.2 to about 1.8or about 1.4 to about 1.5; (e) the composition has a specific gravity(20° C.) of about 0.8 to about 1.0, about 0.85 to about 0.95 or about0.9 to about 0.92; (e) the composition contains not more than about 20ppm, not more than about 15 ppm or not more than about 10 ppm heavymetals, (0 the composition contains not more than about 5 ppm, not morethan about 4 ppm, not more than about 3 ppm, or not more than about 2ppm arsenic, and/or (g) the composition has a peroxide value of not morethan about 5 meq/kg, not more than about 4 meq/kg, not more than about 3meq/kg, or not more than about 2 meq/kg.

In another embodiment, compositions useful in accordance with methods ofthe invention are orally deliverable. The terms “orally deliverable” or“oral administration” herein include any form of delivery of atherapeutic agent or a composition thereof to a subject wherein theagent or composition is placed in the mouth of the subject, whether ornot the agent or composition is swallowed. Thus “oral administration”includes buccal and sublingual as well as esophageal administration. Inone embodiment, the composition is present in a capsule, for example asoft gelatin capsule.

A composition for use in accordance with the invention can be formulatedas one or more dosage units. The terms “dose unit” and “dosage unit”herein refer to a portion of a pharmaceutical composition that containsan amount of a therapeutic agent suitable for a single administration toprovide a therapeutic effect. Such dosage units may be administered oneto a plurality (i.e. 1 to about 10, 1 to 8, 1 to 6, 1 to 4 or 1 to 2) oftimes per day, or as many times as needed to elicit a therapeuticresponse.

In one embodiment, compositions of the invention, upon storage in aclosed container maintained at room temperature, refrigerated (e.g.about 5 to about 5-10° C.) temperature, or frozen for a period of about1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months, exhibit at least about90%, at least about 95%, at least about 97.5%, or at least about 99% ofthe active ingredient(s) originally present therein.

Therapeutic Methods

In one embodiment, the invention provides a method for treatment and/orprevention of cardiovascular-related disease and disorders. The term“cardiovascular-related disease and disorders” herein refers to anydisease or disorder of the heart or blood vessels (i.e. arteries andveins) or any symptom thereof. Non-limiting examples ofcardiovascular-related disease and disorders includehypertriglyceridemia, hypercholesterolemia, mixed dyslipidemia, coronaryheart disease, vascular disease, stroke, atherosclerosis, arrhythmia,hypertension, myocardial infarction, and other cardiovascular events.

The term “treatment” in relation a given disease or disorder, includes,but is not limited to, inhibiting the disease or disorder, for example,arresting the development of the disease or disorder; relieving thedisease or disorder, for example, causing regression of the disease ordisorder; or relieving a condition caused by or resulting from thedisease or disorder, for example, relieving, preventing or treatingsymptoms of the disease or disorder. The term “prevention” in relationto a given disease or disorder means: preventing the onset of diseasedevelopment if none had occurred, preventing the disease or disorderfrom occurring in a subject that may be predisposed to the disorder ordisease but has not yet been diagnosed as having the disorder ordisease, and/or preventing further disease/disorder development ifalready present.

In various embodiments, the present invention provides methods ofreducing a risk of a cardiovascular event in a subject on statintherapy. In some embodiments, the method comprises (a) identifying asubject on statin therapy and having a fasting baseline triglyceridelevel of about 135 mg/dL to about 500 mg/dL, wherein said subject hasestablished cardiovascular disease or has a high risk of developingcardiovascular disease; and (b) administering to the subject apharmaceutical composition comprising about 1 g to about 4 g ofeicosapentaenoic acid ethyl ester per day, wherein the compositioncontains substantially no docosahexaenoic acid.

In some embodiments, the subject has a fasting baseline triglyceridelevel of about 135 mg/dL to about 500 mg/dL, for example 135 mg/dL to500 mg/dL, 150 mg/dL to 500 mg/dL, or 200 mg/dL to <500 mg/dL. In someembodiments, the subject or subject group has a baseline triglyceridelevel (or median baseline triglyceride level in the case of a subjectgroup), fed or fasting, of about 135 mg/dL, about 140 mg/dL, about 145mg/dL, about 150 mg/dL, about 155 mg/dL, about 160 mg/dL, about 165mg/dL, about 170 mg/dL, about 175 mg/dL, about 180 mg/dL, about 185mg/dL, about 190 mg/dL, about 195 mg/dL, about 200 mg/dL, about 205mg/dL, about 210 mg/dL, about 215 mg/dL, about 220 mg/dL, about 225mg/dL, about 230 mg/dL, about 235 mg/dL, about 240 mg/dL, about 245mg/dL, about 250 mg/dL, about 255 mg/dL, about 260 mg/dL, about 265mg/dL, about 270 mg/dL, about 275 mg/dL, about 280 mg/dL, about 285mg/dL, about 290 mg/dL, about 295 mg/dL, about 300 mg/dL, about 305mg/dL, about 310 mg/dL, about 315 mg/dL, about 320 mg/dL, about 325mg/dL, about 330 mg/dL, about 335 mg/dL, about 340 mg/dL, about 345mg/dL, about 350 mg/dL, about 355 mg/dL, about 360 mg/dL, about 365mg/dL, about 370 mg/dL, about 375 mg/dL, about 380 mg/dL, about 385mg/dL, about 390 mg/dL, about 395 mg/dL, about 400 mg/dL, about 405mg/dL, about 410 mg/dL, about 415 mg/dL, about 420 mg/dL, about 425mg/dL, about 430 mg/dL, about 435 mg/dL, about 440 mg/dL, about 445mg/dL, about 450 mg/dL, about 455 mg/dL, about 460 mg/dL, about 465mg/dL, about 470 mg/dL, about 475 mg/dL, about 480 mg/dL, about 485mg/dL, about 490 mg/dL, about 495 mg/dL, or about 500 mg/dL.

In some embodiments, the subject or subject group is also on stabletherapy with a statin (with or without ezetimibe). In some embodiments,the subject or subject group also has established cardiovasculardisease, or is at high risk for establishing cardiovascular disease. Insome embodiments, the subject's statin therapy includes administrationof one or more statins. For example and without limitation, thesubject's statin therapy may include one or more of: atorvastatin,fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, andsimvastatin. In some embodiments, the subject is additionallyadministered one or more of: amlodipine, ezetimibe, niacin, andsitagliptin. In some embodiments, the subject's statin therapy includesadministration of a statin and ezetimibe. In some embodiments, thesubject's statin therapy includes administration of a statin withoutezetimibe.

In some embodiments, the subject's statin therapy does not includeadministration of 200 mg or more per day of niacin and/or fibrates. Insome embodiments, the subject is not on concomitant omega-3 fatty acidtherapy (e.g., is not being administered or co-administered aprescription and/or over-the-counter composition comprising an omega-3fatty acid active agent). In some embodiments, the subject is notadministered or does not ingest a dietary supplement comprising anomega-3 fatty acid.

In some embodiments, the subject has established cardiovascular disease(“CV disease” or “CVD”). The status of a subject as having CV diseasecan be determined by any suitable method known to those skilled in theart. In some embodiments, a subject is identified as having establishedCV disease by the presence of any one of: documented coronary arterydisease, documented cerebrovascular disease, documented carotid disease,documented peripheral arterial disease, or combinations thereof. In someembodiments, a subject is identified as having CV disease if the subjectis at least 45 years old and: (a) has one or more stenosis of greaterthan 50% in two major epicardial coronary arteries; (b) has had adocumented prior MI; (c) has been hospitalized for high-risk NSTE ACSwith objective evidence of ischemia (e.g., ST-segment deviation and/orbiomarker positivity); (d) has a documented prior ischemic stroke; (e)has symptomatic artery disease with at least 50% carotid arterialstenosis; (0 has asymptomatic carotid artery disease with at least 70%carotid arterial stenosis per angiography or duplex ultrasound; (g) hasan ankle-brachial index (“ABI”) of less than 0.9 with symptoms ofintermittent claudication; and/or (h) has a history of aorto-iliac orperipheral arterial intervention (catheter-based or surgical).

In some embodiments, the subject or subject group being treated inaccordance with methods of the invention has a high risk for developingCV disease. For example and without limitation, a subject or subjectgroup has a high risk for developing CV disease if the subject orsubject in a subject group is age 50 or older, has diabetes mellitus(Type 1 or Type 2), and at least one of: (a) is a male age 55 or olderor a female age 65 or older; (b) is a cigarette smoker or was acigarette smoker who stopped less than 3 months prior; (c) hashypertension (e.g., a blood pressure of 140 mmHg systolic or higher, orgreater than 90 mmHg diastolic); (d) has an HDL-C level of ≤40 mg/dL formen or ≤50 mg/dL for women; (e) has an hs-CRP level of >3.0 mg/L; (0 hasrenal dysfunction (e.g., a creatinine clearance (“CrCL”) of greater than30 mL/min and less than 60 mL/min); (g) has retinopathy (e.g., definedas any of: non-proliferative retinopathy, preproliferative retinopathy,proliferative retinopathy, maculopathy, advanced diabetic eye disease,or history of photocoagulation); (h) has microalbuminuria (e.g., apositive micral or other strip test, an albumin/creatinine ratio of ≥2.5mg/mmol, or an albumin excretion rate on timed collection of ≥20 mg/minall on at least two successive occasions); (i) has macroalbuminuria(e.g., albumix or other dip stick evidence of gross proteinuria, analbumin/creatinine ratio of ≥25 mg/mmol, or an albumin excretion rate ontimed collection of ≥200 mg/min all on at least two successiveoccasions); and/or (j) has an ankle-brachial index of <0.9 withoutsymptoms of intermittent claudication.

In some embodiments, the subject's baseline lipid profile is measured ordetermined prior to administering the pharmaceutical composition to thesubject. Lipid profile characteristics can be determined by any suitablemethod known to those skilled in the art including, for example, bytesting a fasting or non-fasting blood sample obtained from the subjectusing standard blood lipid profile assays. In some embodiments, thesubject has one or more of: a baseline non-HDL-C value of about 200mg/dL to about 300 mg/dL; a baseline total cholesterol value of about250 mg/dL to about 300 mg/dL; a baseline VLDL-C value of about 140 mg/dLto about 200 mg/dL; a baseline HDL-C value of about 10 to about 30mg/dL; and/or a baseline LDL-C value of about 40 to about 100 mg/dL.

In some embodiments, the cardiovascular event for which risk is reducedis one or more of: cardiovascular death; nonfatal myocardial infarction;nonfatal stroke; coronary revascularization; unstable angina (e.g.,unstable angina determined to be caused by myocardial ischemia by, forexample, invasive or non-invasive testing, and requiringhospitalization); cardiac arrest; peripheral cardiovascular diseaserequiring intervention, angioplasty, bypass surgery or aneurysm repair;death; and onset of new congestive heart failure.

In some embodiments, the subject is administered about 1 g to about 4 gof the pharmaceutical composition per day for about 4 months, about 1year, about 2 years, about 3 years, about 4 years, about 5 years, ormore than about 5 years. Thereafter, in some embodiments the subjectexhibits one or more of

(a) reduced triglyceride levels compared to baseline;

(b) reduced Apo B levels compared to baseline;

(c) increased HDL-C levels compared to baseline;

(d) no increase in LDL-C levels compared to baseline;

(e) a reduction in LDL-C levels compared to baseline;

(f) a reduction in non-HDL-C levels compared to baseline;

(g) a reduction in VLDL levels compared to baseline;

(h) a reduction in total cholesterol levels compared to baseline;

(i) a reduction in high sensitivity C-reactive protein (hs-CRP) levelscompared to baseline; and/or

(j) a reduction in high sensitivity troponin (hsTnT) levels compared tobaseline.

In some embodiments, the subject exhibits one or more of: (a) areduction in triglyceride level of at least about 5%, at least about10%, at least about 15%, at least about 20%, at least about 25%, atleast about 30%, at least about 35%, at least about 40%, at least about45%, at least about 50%, or at least about 55% as compared to baseline;

(b) a less than 30% increase, less than 20% increase, less than 10%increase, less than 5% increase or no increase in non-HDL-C levels or areduction in non-HDL-C levels of at least about 1%, at least about 3%,at least about 5%, at least about 10%, at least about 15%, at leastabout 20%, at least about 25%, at least about 30%, at least about 35%,at least about 40%, at least about 45%, or at least about 50% ascompared to baseline;

(c) an increase in HDL-C levels of at least about 5%, at least about10%, at least about 15%, at least about 20%, at least about 25%, atleast about 30%, at least about 35%, at least about 40%, at least about45%, or at least about 50% as compared to baseline; and/or

(d) a less than 30% increase, less than 20% increase, less than 10%increase, less than 5% increase or no increase in LDL-C levels or areduction in LDL-C levels of at least about 5%, at least about 10%, atleast about 15%, at least about 20%, at least about 25%, at least about30%, at least about 35%, at least about 40%, at least about 45%, atleast about 50%, or at least about 55% as compared to baseline.

In one embodiment, the subject or subject group being treated has abaseline EPA blood level on a (mol %) basis of less than 2.6, less than2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1, lessthan 2, less than 1.9, less than 1.8, less than 1.7, less than 1.6, lessthan 1.5, less than 1.4, less than 1.3, less than 1.2, less than 1.1 orless than 1.

In another embodiment, the subject or subject group being treated has abaseline triglyceride level (or median baseline triglyceride level inthe case of a subject group), fed or fasting, of about 135 mg/dL toabout In some embodiments, the subject or subject group being treated inaccordance with methods of the invention is on stable therapy with astatin (with or without ezetimibe). As used herein, the phrase “onstable therapy with a statin” means that the subject or subject grouphas been on the same daily dose of the same statin for at least 28 daysand, if applicable, the same daily dose of ezetimibe for at least 28days. In some embodiments, the subject or subject group on stable statintherapy has an LDL-C level of about 40 mg/dL to about 100 mg/dL.

In some embodiments, safety laboratory tests of subject blood samplesinclude one or more of: hematology with complete blood count (“CBC”),including RBC, hemoglobin (Hgb), hematocrit (Hct), white cell bloodcount (WBC), white cell differential, and platelet count; andbiochemistry panel including total protein, albumin, alkalinephosphatase, alanine aminotransferase (ALT/SGPT), aspartateaminotransferase (AST/SGOT), total bilirubin, glucose, calcium,electrolytes, (sodium, potassium, chloride), blood urea nitrogen (BUN),serum creatinine, uric acid, creatine kinase, and HbA_(1c).

In some embodiments, a fasting lipid panel associated with a subjectincludes TG, TC, LDL-C, HDL-C, non-HDL-C, and VLDL-C. In someembodiments, LDL-C is calculated using the Friedewald equation, or ismeasured by preparative ultracentrifugation (Beta Quant) if thesubject's triglyceride level is greater than 400 mg/dL. In someembodiments, LDL-C is measured by ultracentrifugation (Beta Quant) atrandomization and again after about one year after randomization.

In some embodiments, a biomarker assay associated with blood obtainedfrom a subject includes hs-CRP, Apo B and hsTnT.

In some embodiments, a medical history associated with a subjectincludes family history, details regarding all illnesses and allergiesincluding, for example, date(s) of onset, current status ofcondition(s), and smoking and alcohol use.

In some embodiments, demographic information associated with a subjectincludes day, month and year of birth, race, and gender.

In some embodiments, vital signs associated with a subject includesystolic and diastolic blood pressure, heart rate, respiratory rate, andbody temperature (e.g., oral body temperature).

In some embodiments, a physical examination of a subject includesassessments of the subject's general appearance, skin, head, neck,heart, lung, abdomen, extremities, and neuromusculature.

In some embodiments, the subject's height and weight are measured. Insome embodiments, the subject's weight is recorded with the subjectwearing indoor clothing, with shoes removed, and with the subject'sbladder empty.

In some embodiments, a waist measurement associated with the subject ismeasured. In some embodiments, the waist measurement is determined witha tape measure at the top of the subject's hip bone.

In some embodiments, an electrocardiogram associated with the subject isobtained. In some embodiments, an ECG is obtained every year during thetreatment/follow-up portion of the study. In some embodiments, the ECGis a 12-lead ECG. In some embodiments, the ECG is analyzed for detectionof silent MI.

In some embodiments, subjects randomly assigned to the treatment groupreceive 4 g per day of a composition comprising at least 96% by weightof eicosapentaenoic acid ethyl ester. In some embodiments, thecomposition is encapsulated in a gelatin capsule. In some embodiments,subjects in this treatment group continue to take 4 g per day of thecomposition for about 1 year, about 2 years, about 3 years, about 4years, about 4.75 years, about 5 years, about 6 years, about 7 years,about 8 years, about 9 years, about 10 years, or more than about 10years. In some embodiments, a median treatment duration is planned to beabout 4 years.

In some embodiments, the present invention provides a method of reducinga risk of cardiovascular events in a subject. In some embodiments, themethod comprises administering to the subject a composition comprisingat least 96% by weight of eicosapentaenoic acid ethyl ester. In someembodiments, the subject is administered about 1 g to about 4 g of thecomposition per day.

In some embodiments, the reduced risk of CV events is indicated ordetermined by comparing an amount of time (e.g., an average amount oftime) associated with a subject or subject group from first dosing to afirst CV event selected from the group consisting of: CV death, nonfatalMI, nonfatal stroke, coronary revascularization, and hospitalization(e.g., emergent hospitalization) for unstable angina determined to becaused by myocardial ischemia (e.g., by invasive or non-invasivetesting), to an amount of time (e.g., an average amount of time)associated with a placebo or untreated subject or group of subjects fromfirst dosing with a placebo to a first CV event selected from the groupconsisting of: CV death, nonfatal MI, nonfatal stroke, coronaryrevascularization, and hospitalization (e.g., emergent hospitalization)for unstable angina determined to be caused by myocardial ischemia(e.g., by invasive or non-invasive testing), wherein said placebo doesnot include eicosapentaenoic acid ethyl ester. In some embodiments, theamount of time associated with the subject or group of subjects arecompared to the amount of time associated with the placebo or untreatedsubject or group of subjects are compared using a log-rank test. In someembodiments, the log-rank test includes one or more stratificationfactors such as CV Risk Category, use of ezetimibe, and/or geographicalregion.

In some embodiments, the present invention provides a method of reducingrisk of CV death in a subject on stable statin therapy and having CVdisease or at high risk for developing CV disease, comprisingadministering to the subject a composition as disclosed herein.

In another embodiment, the present invention provides a method ofreducing risk of recurrent nonfatal myocardial infarction (includingsilent MI) in a subject on stable statin therapy and having CV diseaseor at high risk for developing CV disease, comprising administering tothe patient one or more compositions as disclosed herein.

In some embodiments, the present invention provides a method of reducingrisk of nonfatal stroke in a subject on stable statin therapy and havingCV disease or at high risk for developing CV disease, comprisingadministering to the subject a composition as disclosed herein.

In some embodiments, the present invention provides a method of reducingrisk of coronary revascularization in a subject on stable statin therapyand having CV disease or at high risk for developing CV disease,comprising administering to the subject a composition as disclosedherein.

In some embodiments, the present invention provides a method of reducingrisk of developing unstable angina caused by myocardial ischemia in asubject on stable statin therapy and having CV disease or at high riskfor developing CV disease, comprising administering to the subject acomposition as disclosed herein.

In another embodiment, any of the methods disclosed herein are used intreatment or prevention of a subject or subjects that consume atraditional Western diet. In one embodiment, the methods of theinvention include a step of identifying a subject as a Western dietconsumer or prudent diet consumer and then treating the subject if thesubject is deemed a Western diet consumer. The term “Western diet”herein refers generally to a typical diet consisting of, by percentageof total calories, about 45% to about 50% carbohydrate, about 35% toabout 40% fat, and about 10% to about 15% protein. A Western diet mayalternately or additionally be characterized by relatively high intakesof red and processed meats, sweets, refined grains, and desserts, forexample more than 50%, more than 60% or more or 70% of total caloriescome from these sources.

In another embodiment, a composition as described herein is administeredto a subject once or twice per day. In another embodiment, 1, 2, 3 or 4capsules, each containing about 1 g of a composition as describedherein, are administered to a subject daily. In another embodiment, 1 or2 capsules, each containing about 1 g of a composition as describedherein, are administered to the subject in the morning, for examplebetween about 5 am and about 11 am, and 1 or 2 capsules, each containingabout 1 g of a composition as described herein, are administered to thesubject in the evening, for example between about 5 pm and about 11 pm.

In some embodiments, the risk of a cardiovascular event in a subject isreduced compared to a control population. In some embodiments, aplurality of control subjects to a control population, wherein eachcontrol subject is on stable statin therapy, has a fasting baselinetriglyceride level of about 135 mg/dL to about 500 mg/dL, and hasestablished cardiovascular disease or a high risk of developingcardiovascular disease, and wherein the control subjects are notadministered the pharmaceutical composition comprising about 1 g toabout 4 g of eicosapentaenoic acid ethyl ester per day.

In some embodiments, a first time interval beginning at (a) an initialadministration of a composition as disclosed herein to the subject to(b) a first cardiovascular event of the subject is greater than orsubstantially greater than a first control time interval beginning at(a′) initial administration of a placebo to the control subjects to (b′)a first cardiovascular event in the control subjects. In someembodiments, the first cardiovascular event of the subject is a majorcardiovascular event selected from the group consisting of:cardiovascular death, nonfatal myocardial infarction, nonfatal stroke,coronary revascularization, and unstable angina caused by myocardialischemia. In some embodiments, the first cardiovascular event of thecontrol subjects is a major cardiovascular event selected from the groupconsisting of: cardiovascular death, nonfatal myocardial infarction,nonfatal stroke, coronary revascularization, and unstable angina causedby myocardial ischemia. In some embodiments, the first cardiovascularevent of the subject and the first cardiovascular event of the controlsubjects is any of: death (from any cause), nonfatal myocardialinfarction, or nonfatal stroke. In some embodiments, the firstcardiovascular event of the subject and the first cardiovascular eventof the control subjects is any of: death from a cardiovascular cause,nonfatal myocardial infarction, coronary revascularization, unstableangina, peripheral cardiovascular disease, or cardiac arrhythmiarequiring hospitalization. In some embodiments, the first cardiovascularevent of the subject and the first cardiovascular event of the controlsubjects is any of: death from a cardiovascular cause, nonfatalmyocardial infarction, and coronary revascularization, unstable angina.In some embodiments, the first cardiovascular event of the subject andthe first cardiovascular event of the control subjects is any of: deathfrom a cardiovascular cause and nonfatal myocardial infarction. In someembodiments, the first cardiovascular event of the subject and the firstcardiovascular event of the control subjects is death (from any cause).In some embodiments, the first cardiovascular event of the subject andthe first cardiovascular event of the control subjects is any of: fatalmyocardial infarction and nonfatal myocardial infarction (optionallyincluding silent MI). In some embodiments, the first cardiovascularevent of the subject and the first cardiovascular event of the controlsubjects is coronary revascularization. In some embodiments, the firstcardiovascular event of the subject and the first cardiovascular eventof the control subjects is hospitalization (e.g. emergenthospitalization) for unstable angina (optionally unstable angina causedby myocardial ischemia). In some embodiments, the first cardiovascularevent of the subject and the first cardiovascular event of the controlsubjects is any one of: fatal stroke or nonfatal stroke. In someembodiments, the first cardiovascular event of the subject and the firstcardiovascular event of the control subjects is any one of: new coronaryheart failure, new coronary heart failure leading to hospitalization,transient ischemic attack, amputation for coronary vascular disease, andcarotid revascularization. In some embodiments, the first cardiovascularevent of the subject and the first cardiovascular event of the controlsubjects is any one of: elective coronary revascularization and emergentcoronary revascularization. In some embodiments, the firstcardiovascular event of the subject and the first cardiovascular eventof the control subjects is an onset of diabetes. In some embodiments,the first cardiovascular event of the subject and the firstcardiovascular event of the control subjects is cardiac arrhythmiarequiring hospitalization. In some embodiments, the first cardiovascularevent of the subject and the first cardiovascular event of the controlsubjects is cardiac arrest.

In some embodiments, a second time interval beginning at (a) an initialadministration of the pharmaceutical composition to the subject to (c) asecond cardiovascular event of the subject is greater than orsubstantially greater than a second control time interval beginning at(a′) initial administration of a placebo to the control subjects to (c′)a second cardiovascular event in the control subjects. In someembodiments, the second cardiovascular event of the subject and thesecond cardiovascular event of the control subjects is a majorcardiovascular event selected from the group consisting of:cardiovascular death, nonfatal myocardial infarction, nonfatal stroke,coronary revascularization, and unstable angina caused by myocardialischemia.

In some embodiments, the subject has diabetes mellitus and the controlsubjects each have diabetes mellitus. In some embodiments, the subjecthas metabolic syndrome and the control subjects each have metabolicsyndrome.

In some embodiments, the subject exhibits one or more of (a) reducedtriglyceride levels compared to the control population; (b) reduced ApoB levels compared to the control population; (c) increased HDL-C levelscompared to the control population; (d) no increase in LDL-C levelscompared to the control population; (e) a reduction in LDL-C levelscompared to the control population; (f) a reduction in non-HDL-C levelscompared to the control population; (g) a reduction in VLDL levelscompared to the control population; (h) a reduction in total cholesterollevels compared to the control population; (i) a reduction in highsensitivity C-reactive protein (hs-CRP) levels compared to the controlpopulation; and/or (j) a reduction in high sensitivity troponin (hsTnT)levels compared to the control population.

In some embodiments, the subject's weight after administration of thecomposition is less than a baseline weight determined beforeadministration of the composition. In some embodiments, the subject'swaist circumference after administration of the composition is less thana baseline waist circumference determined before administration of thecomposition.

In methods of the present invention in which a time interval isdetermined or assessed, the time interval may be for example an average,a median, or a mean time interval. For example, in embodiments wherein afirst control time interval is associated with a plurality of controlsubjects, the first control time interval is an average, a median, or amean of a plurality of first control time intervals associated with eachcontrol subject. Similarly, in embodiments wherein a second control timeinterval is associated with a plurality of control subjects, the secondcontrol time interval is an average, a median, or a mean of a pluralityof second control time intervals associated with each control subject.

In some embodiments, the reduced risk of cardiovascular events isexpressed as a difference in incident rates between a study group and acontrol population. In some embodiments, the subjects in the study groupexperience a first major cardiovascular event after an initialadministration of a composition as disclosed herein at a first incidencerate which is less than a second incidence rate, wherein the secondincidence rate is associated with the rate of cardiovascular events inthe subjects in the control population. In some embodiments, the firstmajor cardiovascular event is any one of: cardiovascular death, nonfatalmyocardial infarction, nonfatal stroke, coronary revascularization, andhospitalization for unstable angina (optionally determined to be causedby myocardial ischemia). In some embodiments, the first and secondincidence rates are determined for a time period beginning on the dateof the initial administration and ending about 4 months, about 1 year,about 2 years, about 3 years, about 4 years, or about 5 years after thedate of initial administration.

In another embodiment, the invention provides use of any compositiondescribed herein for treating hypertriglyceridemia in a subject in needthereof, comprising: providing a subject having a fasting baselinetriglyceride level of about 135 mg/dL to about 500 mg/dL andadministering to the subject a pharmaceutical composition as describedherein. In one embodiment, the composition comprises about 1 g to about4 g of eicosapentaenoic acid ethyl ester, wherein the compositioncontains substantially no docosahexaenoic acid.

EXAMPLES

A phase 3, multi-center, placebo-controlled randomized, double-blind,12-week study with an open-label extension is performed to evaluate theefficacy and safety of AMR101 in patients with fasting triglyceridelevels ≥150 mg/dL and <500 mg/dL. The primary objective is, in patientsat LDL-C goal while on statin therapy, with established cardiovasculardisease (CVD) or at high risk for CVD, and hypertriglyceridemia (fastingtriglycerides, TG, ≥200 mg/dL and <500 mg/dL, determine the efficacy ofAMR101 4 g daily, compared to placebo, in preventing the occurrence of afirst major cardiovascular event of the composite endpoint thatincludes:

-   -   cardiovascular (“CV”) death;    -   nonfatal myocardial infarction (“MI”);    -   nonfatal stroke;    -   coronary revascularization; and    -   unstable angina determined to be caused by myocardial ischemia        by invasive/non-invasive testing and requiring emertgent        hospitalization.

The secondary objectives of this study are the following:

To evaluate the effect of therapy on the composite of death from CVcauses, nonfatal MI, coronary revascularization, unstable anginadetermined to be caused by myocardial ischemia by invasive/non-invasivetesting and requiring emergent hospitalization, nonfatal stroke, orperipheral CV disease requiring intervention, angioplasty, bypasssurgery, and aneurysm repair;

To evaluate the effect of therapy on combinations of each of theclinical events listed in secondary objective #1, supra, in addition tocardiac arrhythmia requiring hospitalization, cardiac arrest, peripheralCV disease requiring intervention, angioplasty, bypass surgery, aneurysmrepair, and total mortality;

To evaluate the effect of therapy on the occurrence of a second, third,fourth and fifth major cardiovascular event (e.g., occurrence of CVdeath, nonfatal MI, nonfatal stroke, coronary revascularization, andunstable angina determined to be caused by myocardial ischemia byinvasive/non-invasive testing and requiring emergent hospitalizationafter a first occurrence of any of same);

To evaluate the effect of therapy on the first occurrence of a majorcardiovascular event in subgroups of patients including (a) those withdiabetes mellitus, and (b) those with metabolic syndrome (e.g., asdefined by the NCEP ATP III or future criteria as may evolve therefrom);

To evaluate the effect of therapy on new congestive heart failure(“CHF”), on new CHF as a primary cause of hospitalization, on transientischemic attack, on amputation for CV disease, and on carotidrevascularization;

To evaluate the effect of therapy on occurrence of elective coronaryrevascularization and emergent coronary revascularization;

To evaluate the effects of therapy on lipids, lipoproteins andinflammatory markers including triglycerides, total cholesterol,low-density lipoprotein cholesterol (“LDL-C”), high-density lipoproteincholesterol (“HDL-C”), non-HDL-C, very low-density lipoproteincholesterol (“VLDL-C”), apoliporpotein B (“apo B”), high-sensitivityC-reactive protein (“hs-CRP”), and high-sensitivity troponin (“hsTnT”)as follows:

Evaluation of the effect of therapy on each marker;

Evaluation of the effect of the baseline value of each marker on therapyeffects; and

Evaluation of the effect of therapy for preventing clinical events asdefined above among all patients in the study and in sub-groups such aspatients with diabetes mellitus and patients with substantialon-treatment changes of any of the markers;

To evaluate the effect of therapy on new onset diabetes; and

To explore the effect of therapy on weight and waist circumference.

Study Population

The population for this study is men and women ≥45 years of age withestablished CVD, or men and women ≥50 years of age with diabetes incombination with one additional risk factor for CVD. In addition, allpatients will have atherogenic dyslipidemia defined as on treatment forhypercholesterolemia (but at treatment goal for LDL-C, by treatment witha statin) and hypertriglyceridemia. More details are listed in theinclusion criteria.

The patients will need to provide consent to participate in the studyand be willing and able to comply with the protocol and the studyprocedures.

Study Periods

This study consists of the following study periods:

Screening Period: During the screening period, patients will beevaluated for inclusion/exclusion criteria.

At the first visit to the Research Unit (Visit 1), study procedures willbe performed for evaluation of patient's eligibility in the study. Atthis screening visit, patients will sign an informed consent form beforeany study procedure is performed; the informed consent form will coverthe treatment/follow-up period. Based on the evaluation from Visit 1,the following situations may occur:

Patients who are eligible for participation based on the studyprocedures on Visit 1 will return to the Research Unit for Visit 2(randomization visit) to start the treatment/follow-up period. This caseincludes, for example, patients at Visit 1 who are on a stable dose of astatin, are planning to stay on the same statin and the same dose of thestatin, and who not need to wash out any non-statin lipid-alteringmedications.

Patients who are not eligible for participation based on the studyprocedures on Visit 1 and are unlikely to become eligible in the next 28days (for example: unlikely to stabilize statin dose, unable to wash outnon-statin lipid-altering medications, etc.): these patients will bescreen failed after Visit 1.

Patients not eligible for participation in the study based on the studyprocedures on Visit 1 may possibly become eligible in the next 28 days:these patients may return at the discretion of the investigator for asecond optional screening visit (Visit 1.1) at which time the proceduresneeded for re-evaluation of the previously failed inclusion/exclusioncriteria will be repeated. This case includes, for example, patients whoare started on a statin at Visit 1, whose statin dose is changed atVisit 1, and/or needed to wash out non-statin lipid-alteringmedications. The following applies for these patients:

Patients with a change in the statin or statin dose on Visit 1 will needto be on a stable statin dose for at least 28 days before the lipidqualifying measurements at Visit 1.1. Other concomitant medications(antidiabetic therapy, for example) can be optimized or stabilizedduring this period.

Patients starting a washout at Visit 1 will have a washout period of atleast 28 days (only 7 days for bile acid sequestrants) before the lipidqualifying measurements at Visit 1.1.

Patients at Visit 1 who are on a stable dose of a statin, are planningto stay on the same statin at the same dose, and who do not need anymedication washout, but were asked to return for Visit 1.1 to repeat oneor more of the other study procedures not related to concomitantmedications

Patients who become eligible for participation based on the additionalstudy procedures at Visit 1.1 will return to the Research Unit for Visit2 (randomization visit) to start the treatment/follow-up period.

At the end of the screening period, patients will need to meet allinclusion/exclusion criteria before they can be randomized. Patients whoare not eligible for participation after the screening period (based onstudy procedures at Visit 1 and/or Visit 1.1) may return at a later datefor rescreening. These patients will need to re-start with allprocedures starting with Visit 1. This includes patients who need moretime to stabilize one or more conditions or therapies (for example:statin, antidiabetic, antihypertensive, thyroid hormone, HIV-proteaseinhibitor therapy).

Treatment/Follow-Up Period: Within 42 days after the first screeningvisit (Visit 1) or within 60 days after the first screening visit(Visit 1) for those patients that have a second screening visit (Visit1.1), eligible patients will enter the treatment/follow-up period.During this period, the patients will receive study drug during theplanned visits at the Research Site and take the study drug while awayfrom the Research Site.

During the visits, study procedures will be performed for evaluation ofefficacy and safety. A detailed schedule of procedures is provided inTable 1.

Study Duration

The estimated study duration includes a planned 18-month enrollmentperiod followed by a follow-up period of approximately 3.5 years inexpected duration (approximately 5 years in total). Patients will berandomized at different times during the enrollment period but will allend the study at the same date (study end date). It is planned that allrandomized patients will receive study medication and be followed-upuntil the study end date. This is an event-driven trial and patientswill continue in the trial if the trial runs longer than expected, orwill terminate earlier if the trial runs shorter than expected.

The total duration of the trial is based on a median 4-year follow-upperiod across patients. The first patient randomized would be followedfor 4.75 years (the longest individual follow-up duration), and the lastpatient randomized would be followed for 3.25 year (the shortestindividual follow-up duration).

Study Groups

At Visit 2 (Day 0), eligible study patients will be randomly assigned tothe following treatment groups:

Group 1: AMR101 4 g daily (four 1000 mg capsules daily)

Group 2: placebo (four capsules daily)

The four AMR101 or placebo capsules daily will be taken as two capsulesin the morning and two capsules in the evening (twice-per-day dosingregimen).

Number of Patients

This is an event-driven trial: It is expected that a minimum of 1612primary efficacy endpoint events will be required during the study. Atotal of approximately 7990 patients will be entered into the study toeither receive AMR101 or placebo (approximately 3995 patients pertreatment group) in order to observe an estimated 1612 events that makeup the primary composite endpoint for efficacy.

Number of Study Sites

Participants will be enrolled at multiple Research Sites in multiplecountries.

Randomization

On Day 0, eligible patients will be randomized to one of 2 study groupsusing a computer-generated randomization schema. Randomized treatmentassignment to either AMR101 or placebo in a 1:1 ratio will be providedusing the internet (IWR).

Blinding

This is a double-blind study. Patients, investigators, pharmacists andother supporting staff at the Research Sites, personnel and designees ofthe Sponsor, study administrators and personnel at the organization(s)and vendors supporting the study will be unaware of the randomizationcode (i.e., they will not know which study participants are receivingthe experimental drug and which are receiving the placebo drug). Thestudy medication AMR101 and placebo capsules will be similar in size andappearance to maintain blinding.

During the double-blind treatment/follow-up period, everyone (patients,investigators, pharmacists and other supporting staff at the ResearchSites, personnel and designees of the Sponsor, study administrators andpersonnel at the organization(s) and vendors managing/supporting thestudy), with the exception of the laboratory personnel performing theanalysis, will be blinded to individual results of the efficacylaboratory measurements (including lipid values). Individual resultsfrom the lipid profile may be unblinded in the event of an emergency fora patient.

Stratification

Participants will be assigned to treatment groups stratified by CV riskcategory, use of ezetimibe and by geographical region (Westernized,Eastern European, and Asia Pacific countries). There are two CV riskcategories:

CV Risk Category 1: patients with established CVD defined in theinclusion criteria. Patients with diabetes and established CVD areincluded in this category.

CV Risk Category 2: patients with diabetes and at least one additionalrisk factor for CVD, but no established CVD.

Stratification will be recorded in the IWR at the time of enrollment.Approximately 70% of randomized patients will be in the CV Risk Category1 and approximately 30% of randomized patients will be in the CV RiskCategory 2. Enrollment with patients of a CV risk category will bestopped when the planned number of patients in that risk category isreached.

Study Population

Inclusion Criteria

Patients meeting the following criteria will be eligible to participatein the study:

Fasting TG levels of ≥200 mg/dL (2.26 mmol/L) and <500 mg/dL (5.64mmol/L).

LDL-C >40 mg/dL (1.04 mmol/L) and ≤100 mg/dL (2.60 mmol/L) and on stabletherapy with a statin (with or without ezetimibe) for at least 4 weeksprior to the LDL-C/TG baseline qualifying measurements for randomization

Stable therapy is defined as the same daily dose of the same statin forat least 28 days before the lipid qualification measurements (TG andLDL-C) and, if applicable, the same daily dose of ezetimibe for at least28 days before the lipid qualification measurements (TG and LDL-C).Patients who have their statin therapy or use of ezetimibe initiated atVisit 1, or have their statin, statin dose and/or ezetimibe dose changedat Visit 1, will need to go through a stabilization period of at least28 days since initiation/change and have their qualifying lipidmeasurements measured (TG and LDL-C) after the washout period (at Visit1.1).

Statins may be administered with or without ezetimibe.

If patients qualify at the first qualification visit (Visit 1) for TGand LDL-C, and meet all other inclusion/exclusion criteria, they may berandomized at Visit 2. If patients don't qualify at the first qualifyingvisit (Visit 1), a second re-qualifying visit (Visit 1.1) is allowed.For some patients, because they need to stabilize medications and/orneed to washout medications, the second re-qualifying visit (Visit 1.1)will be needed after the stabilization/washout period.

Either having established CVD (in CV Risk Category 1) or at high riskfor CVD (in CV Risk Category 2). The CV risk categories are defined asfollows:

CV Risk Category 1: defined as men and women ≥45 years of age with oneor more of the following:

Documented coronary artery disease (CAD; one or more of the followingprimary criteria must be satisfied):

Documented multivessel CAD (>50% stenosis in at least two majorepicardial coronary arteries—with or without antecedentrevascularization)

Documented prior MI

Hospitalization for high-risk NSTE-ACS (with objective evidence ofischemia: ST-segment deviation or biomarker positivity)

Documented cerebrovascular or carotid disease (one of the followingprimary criteria must be satisfied):

Documented prior ischemic stroke

Symptomatic carotid artery disease with ≥50% carotid arterial stenosis

Asymptomatic carotid artery disease with ≥70% carotid arterial stenosisper angiography or duplex ultrasound

History of carotid revascularization (catheter-based or surgical)

Documented peripheral arterial disease (PAD; one or more of thefollowing primary criteria must be satisfied):

ABI <0.9 with symptoms of intermittent claudication

History of aorto-iliac or peripheral arterial intervention(catheter-based or surgical)

OR

CV Risk Category 2: defined as patients with:

Diabetes mellitus (Type 1 or Type 2) requiring treatment with medicationAND

Men and women ≥50 years of age AND

One of the following at Visit 1 (additional risk factor for CVD):

Men ≥55 years of age or women ≥65 years of age;

Cigarette smoker or stopped smoking within 3 months before Visit 1;

Hypertension (blood pressure ≥140 mmHg systolic OR ≥90 mmHg diastolic)or on antihypertensive medication;

HDL-C ≤40 mg/dL for men or ≤50 mg/dL for women;

Hs-CRP >3.00 mg/L (0.3 mg/dL);

Renal dysfunction: CrCL >30 and <60 mL/min (>0.50 and <1.00 mL/sec);

Retinopathy, defined as any of the following: non-proliferativeretinopathy, preproliferative retinopathy, proliferative retinopathy,maculopathy, advanced diabetic eye disease or a history ofphotocoagulation;

Micro- or macroalbuminuria. Microalbuminuria is defined as either apositive micral or other strip test (may be obtained from medicalrecords), an albumin creatinine ratio ≥2.5 mg/mmol or an albuminexcretion rate on timed collection ≥20 mg/min all on at least twosuccessive occasions; macroalbuminuria, defined as albustix or otherdipstick evidence of gross proteinuria, an albumin:creatinine ratio ≥25mg/mmol or an albumin excretion rate on timed collection ≥200 mg/min allon at least two successive occasions;

ABI <0.9 without symptoms of intermittent claudication (patients withABI <0.9 with symptoms of intermittent claudication are counted under CVRisk Category 1).

Patients with diabetes with CVD as defined above are eligible based onthe CVD requirements and will be counted under CV Risk Category 1. Onlypatients with diabetes and no documented CVD as defined above need atleast one additional risk factor as listed, and will be counted under CVRisk Category 2.

Women may be enrolled if all 3 of the following criteria are met:

They are not pregnant;

They are not breastfeeding;

They do not plan on becoming pregnant during the study.

Women of child-bearing potential must have a negative urine pregnancytest before randomization.

Women are not considered to be of childbearing potential if they meetone of the following criteria as documented by the investigator:

They have had a hysterectomy, tubal ligation or bilateral oophorectomyprior to signing the informed consent form;

They are post-menopausal, defined as ≥1 year since their last menstrualperiod or have a follicle-stimulating hormone (FSH) level in amenopausal range.

Women of childbearing potential must agree to use an acceptable methodof avoiding pregnancy from screening to the end of the study, unlesstheir sexual partner(s) is/are surgically sterile or the woman isabstinent.

Understanding of the study procedures, willing to adhere to the studyschedules, and agreement to participate in the study by giving informedconsent prior to screening.

Agree to follow a physician recommended diet and to maintain it throughthe duration of the study.

Exclusion Criteria

Patients are excluded from participation in the study if any of thefollowing criteria apply:

Severe (class IV) heart failure.

Any life-threatening disease expected to result in death within the next2 years (other than CVD).

Active severe liver disease (evaluated at Visit 1): cirrhosis, activehepatitis, ALT or AST >3×ULN, or biliary obstruction withhyperbilirubinemia (total bilirubin >2×ULN).

Hemoglobin A1c >10.0% (or 86 mmol/mol IFCC units) at screening (Visit1). If patients fail this criterion (HbA1c >10.0% or 86 mmol/mol IFCCunits) at Visit 1, they may have their antidiabetic therapy optimizedand be retested at Visit 1.1.

Poorly controlled hypertension: blood pressure ≥200 systolic mmHg OR≥100 mmHg diastolic (despite antihypertensive therapy).

Planned coronary intervention (such as stent placement or heart bypass)or any non-cardiac major surgical procedure. Patients can be(re)evaluated for participation in the trial (starting with Visit 1.1)after their recovery from the intervention/surgery.

Known familial lipoprotein lipase deficiency (Fredrickson Type I),apolipoprotein C-II deficiency, or familial dysbetalipoproteinemia(Fredrickson Type III)].

Participation in another clinical trial involving an investigationalagent within 90 days prior to screening (Visit 1). Patients cannotparticipate in any other investigational medication or medical devicetrial while participating in this study (participation in a registry orobservational study without an additional therapeutic intervention isallowed).

Intolerance or hypersensitivity to statin therapy.

Known hypersensitivity to any ingredients of the study product orplacebo; known hypersensitivity to fish and or shellfish.

History of acute or chronic pancreatitis.

Malabsorption syndrome and/or chronic diarrhea (Note: patients who haveundergone gastric/intestinal bypass surgery are considered to havemalabsorption, hence are excluded; patients who have undergone gastricbanding are allowed to enter the trial).

Non-study drug related, non-statin, lipid-altering medications,supplements or foods:

Patients are excluded if they used niacin >200 mg/day or fibrates duringthe screening period (after Visit 1) and/or plan to use during thestudy; patients who are taking niacin >200 mg/day or fibrates during thelast 28 days before Visit 1 need to go through washout of at least 28days after their last use and have their qualifying lipids measured (TGand LDL-C) after the washout period (Visit 1.1);

Patients are excluded if they take any omega-3 fatty acid medications(prescription medicines containing EPA and/or DHA) during the screeningperiod (after Visit 1) and/or plan to use during the treatment/follow-upperiod of the study. To be eligible for participation in the study,patients who are taking omega-3 fatty acid medications during the last28 days before Visit 1 (except patients in The Netherlands), need to gothrough a washout period of at least 28 days after their last use andhave their qualifying lipids measured (TG and LDL-C) after the washoutperiod (at Visit 1.1);

For patients in The Netherlands only: patients being treated withomega-3 fatty acid medications containing EPA and/or DHA are excluded;no washout is allowed.

Patients are excluded if they use dietary supplements containing omega-3fatty acids (e.g., flaxseed, fish, krill, or algal oils) during thescreening period (after Visit 1) and/or plan to use during thetreatment/follow-up period of the study. To be eligible forparticipation in the study, patients who are taking >300 mg/day omega-3fatty acids (combined amount of EPA and DHA) within 28 days before Visit1 (except patients in The Netherlands), need to go through a washoutperiod of at least 28 days since their last use and have theirqualifying lipid measurements measured (TG and LDL-C) after the washoutperiod (at Visit 1.1);

For patients in The Netherlands only: patients being treated withdietary supplements containing omega-3 fatty acids of >300 mg/day EPAand/or DHA are excluded; no washout is allowed.

Patients are excluded if they use bile acid sequestrants during thescreening period (after Visit 1) and/or plan to use during thetreatment/follow-up period of the study. To be eligible forparticipation in the study, patients who are taking bile acidsequestrants within 7 days before Visit 1, need to go through a washoutperiod of at least 7 days since their last use and have their qualifyinglipid measurements measured (TG and LDL-C) after the washout period (atVisit 1.1);

Other medications (not indicated for lipid alteration):

Treatment with tamoxifen, estrogens, progestins, thyroid hormonetherapy, systemic corticosteroids (local, topical, inhalation, or nasalcorticosteroids are allowed), HIV-protease inhibitors that have not beenstable for ≥28 days prior to the qualifying lipid measurements (TG andLDL-C) during screening. To be eligible for participation in the study,patients who are not taking a stable dose of these medications within 28days before Visit 1, need to go through a stabilization period of atleast 28 days since their last dose change and have their qualifyinglipid measurements measured (TG and LDL-C) after the washout period (atVisit 1.1).

Patients are excluded if they use cyclophosphamide or systemic retinoidsduring the screening period (after Visit 1) and/or plan to use duringthe treatment/follow-up period of the study. To be eligible forparticipation in the study, patients who are taking these medicationswithin 28 days before Visit 1, need to go through a washout period of atleast 28 days since their last use and have their qualifying lipidmeasurements measured (TG and LDL-C) after the washout period (at Visit1.1).

Known to have AIDS (patients who are HIV positive without AIDS areallowed).

Requirement for peritoneal dialysis or hemodialysis for renalinsufficiency or if creatinine clearance (CrCL) <30 mL/min (0.50mL/sec).

Unexplained creatine kinase concentration >5×ULN or creatine kinaseelevation due to known muscle disease (e.g., polymyositis, mitochondrialdysfunction) at Visit 1.

Any condition or therapy which, in the opinion of the investigator,might pose a risk to the patient or make participation in the study notin the patient's best interest.

Drug or alcohol abuse within the past 6 months, and unable/unwilling toabstain from drug abuse and excessive alcohol consumption during thestudy or drinking 5 units or more for men or 4 units or more for womenin any one hour (episodic excessive drinking or binge drinking).Excessive alcohol consumption is on average >2 units of alcohol per day.A unit of alcohol is defined as a 12-ounce (350 mL) beer, 5-ounce (150mL) wine, or 1.5-ounce (45 mL) of 80-proof alcohol for drinks.

Mental/psychological impairment or any other reason to expect patientdifficulty in complying with the requirements of the study orunderstanding the goal and potential risks of participating in the study(evaluated at Visit 1).

Study Procedures

Assessment Schedule

Screening Period

Screening Visit (Visit 1)

Patients will come to the Research Site for Visit 1. They will beinstructed to fast for at least 10 hours before their visit.

If patients qualify for randomization based on the procedures at Visit1, they need to be randomized within 60 days after Visit 1. Thefollowing procedures will be performed at the screening visit:

Obtain signed informed consent

Assign the patient a patient number

Obtain medical, surgical and family history

Record demographics

Obtain height, weight, and body mass index

Obtain vital signs (systolic and diastolic blood pressure, heart rate,respiratory rate, and body temperature)

Obtain a 12-lead electrocardiogram

Evaluate inclusion/exclusion criteria

This includes procedures and (fasting) blood samples (for example,hs-CRP, calculated creatinine clearance) as needed to determine the CVrisk category (see inclusion criteria)

Obtain fasting blood samples for chemistry and hematology testing

Obtain a fasting blood sample for the lipid profile (TG, TC, HDL-C,LDL-C, non-HDL-C, VLDL-C)

Perform a urine pregnancy test on women of childbearing potential

Record concomitant medication(s)

Instruct patient to fast for at least 10 hours prior to the next visit

Screening Visit (Visit 1.1)

Some patients will skip Visit 1.1: Patients who qualify for studyparticipation after Visit 1 because they meet all inclusion criterionand none of the exclusion criteria, may return to the Research Site forVisit 2 to be randomized and to start the treatment/follow-up period ofthe study. For these patients, Visit 2 will occur soon after Visit 1.

Patients, who do not qualify at Visit 1, may return to the Research Sitefor a second qualifying visit (Visit 1.1) at the discretion of theinvestigator. At Visit 1.1, procedures that caused failure ofeligibility at Visit 1 will be repeated. Patients will be eligible forrandomization after Visit 1.1 if they meet all inclusion criteria and ifthey no longer fail the exclusion criteria. If patients are evaluated atVisit 1.1 and qualify for randomization based on the repeated proceduresat Visit 1.1, they need to be randomized within 60 days after Visit 1.

For some patients, Visit 1.1 will be mandatory at least 28 days afterVisit 1 in order to check eligibility. These are patients who at Visit 1started treatment with a statin, changed their statin, changed the dailydose of their statin, started to washout prohibited medications orstarted a stabilization period with certain medications (seeinclusion/exclusion criteria for details). Any of these changes at Visit1 may affect the qualifying lipid levels and therefore, patients willneed to have Visit 1.1 to determine whether they qualify based on lipidlevel requirements (TG and LDL-C) determined at Visit 1. Otherprocedures that caused failure of eligibility at Visit 1 will also berepeated at Visit 1.1.

The following procedures will be performed at the screening visit:

Obtain vital signs (systolic and diastolic blood pressure, heart rate,respiratory rate, and body temperature)

Evaluate inclusion/exclusion criteria; only those evaluations will berepeated that deemed the patient not eligible on Visit 1.

Obtain fasting blood samples for chemistry and hematology testing. Onlythose samples will be obtained that deemed the patient not eligible onVisit 1.

Obtain a fasting blood sample for the lipid profile (TG, TC, HDL-C,LDL-C, non-HDL-C, VLDL-C) if the patient was deemed not eligible onVisit 1. This includes patients who at Visit 1 started treatment with astatin, changed their statin, changed the daily dose of their statin,started to washout prohibited medications or started a stabilizationperiod with certain medications (see inclusion/exclusion criteria fordetails). These patients will have a fasting blood sample collected atVisit 1.1 for the qualifying lipid values (TG and LDL-C), and the TG andLDL-C inclusion criteria will be evaluated.

Record concomitant medication(s)

Treatment/Follow-Up Period

Every attempt should be made to complete the follow-up visits during thedefined window periods.

Randomization visit (Visit 2; Day 0)

Qualified patients will return to the Research Site for Visit 2.

The following procedures will be performed at Visit 2:

Perform physical examination

Obtain weight

Obtain vital signs (systolic and diastolic blood pressure, heart rate,respiratory rate, and body temperature)

Measure waist circumference (one of the factors to diagnose metabolicsyndrome)

Obtain a 12-lead electrocardiogram

Evaluate inclusion/exclusion criteria

Obtain fasting blood samples for:

Chemistry and hematology testing

Lipid profile (baseline)

Biomarker assays (baseline)

Genetic testing (optional blood sample)

Archiving (in countries and at sites approved by IRB/IEC and dependenton country regulations)

Perform a urine pregnancy test on women of childbearing potential (mustbe negative for randomization)

Dispense study drug and record randomization number

Instruct patient on how to take study drug

Administer study drug—Note: Study drug should be taken orally with foodfollowing the collection of all fasting blood samples

Assess for and record adverse events

Record concomitant medication(s)

Instruct patient:

To bring all study supplies with them to the next visit

Not to take study drug on the morning of their next visit

To fast for ≥10 hours prior to the next visit

Visit 3 (Day 120; ˜4 Months)

Patients will return to the Research Site for Visit 3 on Day 120±10days.

The following procedures will be performed:

Perform physical examination

Obtain weight

Obtain vital signs (systolic and diastolic blood pressure, heart rate,respiratory rate, and body temperature)

Obtain fasting blood samples for:

Chemistry and hematology testing

Lipid profile

Review study drug compliance by unused capsule count; discuss with andcounsel patients about compliance if needed

Administer study drug—Note: Study drug should be taken orally with foodfollowing the collection of all fasting blood samples

Assess and record efficacy events

Assess for and record adverse events

Record concomitant medication(s)

Instruct patient:

To bring all study supplies with them to the next visit

Not to take study drug on the morning of their next visit

To fast for ≥10 hours prior to the next visit

Visits 4, 5, 6 and 7

At Visit 4: Day 360±10; Visit 5: Day 720±10; Visit 6: Day 1080±10; andVisit 7: Day 1440±10, the following procedures will be performed:

Perform physical examination

Obtain weight

Obtain vital signs (systolic and diastolic blood pressure, heart rate,respiratory rate, and body temperature)

Measure waist circumference (collected at Visit 5 only)

Obtain a 12-lead electrocardiogram

Obtain fasting blood samples for:

Chemistry and hematology testing

Lipid profile

Biomarker assays (collected at Visit 5 only)

Archiving (in countries and at sites approved by IRB/IEC and dependenton country regulations)

Review study drug compliance by unused capsule count; discuss with andcounsel patients about compliance if needed

Administer study drug—Note: Study drug should be taken orally with foodfollowing the collection of all fasting blood samples

Assess and record efficacy events

Assess for and record adverse events

Record concomitant medication(s)

Instruct patient:

To bring all study supplies with them to the next visit

Not to take study drug on the morning of their next visit

To fast for ≥10 hours prior to the next visit

Additional Visits

The end date of the study is expected for Day 1800 but the actual enddate will be dependent on the determination of the study end date by theDMC. The study end date is determined to be when approximately 1612primary efficacy events have occurred. If the actual study end date islater than the expected end date, additional visits will be plannedbetween Visit 7 and the Last Visit with a maximum of 360±10 days betweenvisits. If the actual study end date is sooner than the expected enddate, fewer visits will occur, and the last visit (See Section 6.1.2.5)will occur sooner.

On additional visits the same procedures will be performed as listed inSection 6.1.2.3. Irrespective of the number of additional visits, afterthe DMC has established the end of the study date, there will be a lastvisit with procedures as listed in Section 6.1.2.5.

Last Visit—End of Study

All patients will complete the study at the same time (within a 30-daywindow after the study end date), irrespective of the date that theywere randomized. The end date of the study is planned for Day 1800 butthe actual end date will be dependent on the determination of the studyend date when approximately 1612 primary efficacy events have occurred(event-driven trial). For each patient, the last visit may occur within30 day after the actual study end date. However, for the efficacyendpoints based on CV events, only events occurring up to and includingthe scheduled actual study end date will be included in the efficacyanalyses.

A final follow-up visit is required for all patients. In the rare casesthat a final follow-up visit cannot occur within the 30-day timeframefollowing the study end date, any attempt to contact the patient must berecorded on a special contact form, until/unless appropriate informationis obtained.

At the Last Visit, the following procedures will be performed:

Perform physical examination

Obtain weight

Obtain vital signs (systolic and diastolic blood pressure, heart rate,respiratory rate, and body temperature)

Measure waist circumference

Obtain a 12-lead electrocardiogram

Obtain fasting blood samples for:

Chemistry and hematology testing

Lipid profile

Biomarker assays

Archiving (in countries and at sites approved by IRB/IEC and dependenton country regulations)

Determine study drug compliance by unused capsule count

Assess and record efficacy events

Assess for and record adverse events

Record concomitant medication(s)

Telephone Follow-up Contact

Site personnel will contact each patient by telephone on the followingstudy days:

Day 60±3 days

Day 180±5 days

Day 270±5 days

Day 450±5 days

Day 540±5 days

Day 630±5 days

Day 810±5 days

Day 900±5 days

Day 990±5 days

Day 1170±5 days

Day 1260±5 days

Day 1350±5 days

Day 1530±5 days

Day 1620±5 days

Day 1710±5 days

If the treatment/follow-up period of the study is extended beyond theexpected end date (Day 1800), additional follow-up phone calls will bemade every 3 months in-between additional visits ±5 days. If thetreatment/follow period of the study is shorter than the expected enddate, less follow-up phone calls will be needed.

Every attempt will be made to talk to each patient within this timeframe.

The following information will be collected from the patient:

Possible efficacy endpoints related to CV events. Patients will be askedto return to the Research Site to assess for any endpoints or eventsidentified.

Adverse events

Concomitant medications

Current address and contact information (update if changed or will bechanging)

Patients will be reminded about the following items:

To take the study medication according to the dosing schedule assigned,with food

When to return to the Research Center for the next visit

To bring the unused study medication to the next visit

To not take study drug on the morning of their next visit

To fast for at least 10 hours prior to the next visit

Laboratory Procedures

Clinical Laboratory Procedures

All clinical laboratory determinations for screening and safety will beperformed by a certified clinical laboratory under the supervision ofthe Sponsor or its designee.

Whenever possible and appropriate, samples for the clinical laboratoryprocedures will be collected after fasting for at least 10 hours. Forthe purposes of this study, fasting is defined as nothing by mouthexcept water (and any essential medications).

The investigator must review and sign all laboratory test reports. Atscreening, patients who have laboratory values that are outside theexclusionary limits specified in the exclusion criteria may not beenrolled in the study (patients can be considered for the study ifvalues are classified as not clinically significant by theinvestigator). After randomization, the investigator will be notified iflaboratory values are outside of their normal range. In this case, theinvestigator will be required to conduct clinically appropriatefollow-up procedures.

Safety Laboratory Tests

The safety laboratory tests include:

Hematology with complete blood count (CBC), including RBC, hemoglobin(Hgb), hematocrit (Hct), white cell blood count (WBC), white celldifferential, and platelet count

Biochemistry panel including total protein, albumin, alkalinephosphatase, alanine aminotransferase (ALT/SGPT), aspartateaminotransferase (AST/SGOT), total bilirubin, glucose, calcium,electrolytes (sodium, potassium, chloride), blood urea nitrogen (BUN),serum creatinine, uric acid, creatine kinase, and HbA1c.

Fasting Lipid Profile

The fasting lipid panel includes: TG, TC, LDL-C, HDL-C, non-HDL-C, andVLDL-C.

At all visits, LDL-C will be calculated using the Friedewald equation.At Visit 1 and Visit 1.1 Direct LDL-C will be used if at the same visitTG >400 mg/dL (4.52 mmol/L). These LDL-C values will be used for theevaluation of the LDL-C inclusion criterion (LDL-C qualifyingmeasurements for randomization) and for the assessment of changes in thestatin therapy when LDL-C is not at goal. At all remaining visits(except Visit 2 and Visit 4) LDL-C will be measured by Direct LDLCholesterol or by Preparative Ultracentrifugation if at the same visitTG >400 mg/dL (4.52 mmol/L). In addition, irrespective of the TG levels,at Visit 2 (0 Months of Follow-up, baseline) and at Visit 4 (12 Monthsof Follow-up), LDL-C will be measured by PreparativeUltracentrifugation. These Preparative Ultracentrifugation LDL-Cmeasurements will be used in the statistical analysis including thecalculation of the percent change from baseline (1 year versusbaseline).

Genetic Testing

A fasting blood sample will be stored for future genetic testing at thediscretion of the sponsor. The specifics of this test will be determinedat a later date. This sample is optional as local regulations mayprohibit genetic samples to be collected or shipped outside the country,or patients may not consent.

Research on genetic testing will look for links between genes andcertain diseases, including their treatment(s) such as medicines andmedical care. The blood samples will be collected in the study centerwith the regular protocol-required labs. Each patient tube with samplefor genetic testing will be labeled with patient number only. The sitewill maintain a Subject Code Identification List for cross-reference.The patient number does not contain any identifiable information (i.e.Patient initials, date of birth, etc). Un-analyzed samples will bestored frozen by the sponsor for a period of up to 2 years following theend of the study, at which time they will be destroyed. If samples aretested, results will not be reported to the patient, parents, relatives,or attending physician and will not be recorded in the patient's medicalrecords. There will be no follow-up contact with the sites or patientsregarding this sample. The subject can withdraw their consent forgenetic testing at any time up to analysis, even after the sample hasbeen obtained. The subject can notify the site in writing that theywithdraw their consent for the genetic testing portion of the study, andit will be documented by the site in the subject chart, as well ascaptured in the CRF. The lab will be notified to pull the sample anddestroy it.

Biomarkers Assays

The biomarker assays include: hs-CRP, Apo B and hsTnT.

Additional laboratory tests

Additional laboratory tests include:

A urine pregnancy test will be administered to women of childbearingpotential at certain visits as listed in schedule of procedures (Table1). The urine pregnancy tests will be performed at the Research Siteutilizing marketed test kits, or at a certified clinical laboratory.

A fasting blood sample (12 mL) for archiving. This sample will becollected only at sites in countries where allowed by local regulationsand at sites for which approved by the IRB or IEC. The plasma from thearchiving sample will be stored frozen in 2 separate equal aliquots, andwill be used at the Sponsor's discretion to perform repeat analysesdescribed in the protocol or to perform other tests related tocardiovascular health.

Blinding of Laboratory Results

All efficacy laboratory results during the double-blind period of thetrial will be blinded (values not provided) to patients, investigators,pharmacists and other supporting staff at the Research Sites, personneland designees of the Sponsor, study administrators and personnel at theorganization(s) and vendors managing and/or supporting the study, withthe exception of the laboratory personnel conducting the assays. Toensure patient safety, hsTnT values will be reported to the site.

Flagging of Critical Lab Values

Critical lab values are values that may warrant medical intervention toavoid possible harm to a patient. Critical lab values will be defined inthe Laboratory Manual for the study, and the Research Site will benotified of the occurrence of a critical lab value (critical high orcritical low) by a special annotation (flag) in the laboratory reportsprovided to the Research Sites. Although laboratory values that are partof the efficacy endpoints during the double-blind period of the studywill not be provided to the Research Site (see Section 6.3.1.6), thesites will be notified when the TG value of a patient sample is >1000mg/dL (11.29 mmol/L) (critical high TG value) or if the LDL-C values ofa patient sample is >130 mg/dL (3.37 mmol/L) (critical high LDL-Cvalue). These critical high values will need to be confirmed by a repeatmeasurement (new fasting blood sample) within 7 days. TG value of >2000mg/dL (22.58 mmol/L) will also be flagged, so that appropriate medicalaction can be taken by the investigator as soon as possible.

If TG values are confirmed critically high, patients may be discontinuedfrom study drug with the option to remain on study. The investigatorshould use the best clinical judgment for each patient which couldinclude the use of approved TG-lowering medications after patients havebeen discontinued from study drug.

If LDL-C values are confirmed critically high, the investigator may needto take appropriate medical action which could include:reinforce/intensify therapeutic lifestyle changes (including diet andphysical activity), increase the dose of the present statin therapy, addezetimibe, or prescribe a more potent statin to lower LDL-C. Theinvestigator should use the best clinical judgment for each patient.

Medical Procedures

Medical, Surgical and Family History

Medical history, including family history and details regarding allillnesses and allergies, date(s) of onset, status of current condition,and smoking and alcohol use will be collected on all patients.

Demographics

Demographic information including day, month, and year of birth, race,and gender will be collected for all patients.

Vital Signs

Vital signs include systolic and diastolic blood pressure, heart rate,respiratory rate, and body temperature. Blood pressure will be measuredusing a standardized process:

Patient should sit for ≥5 minutes with feet flat on the floor andmeasurement arm supported so that the midpoint of the manometer cuff isat heart level.

Use a mercury sphygmomanometer or automatic blood pressure device withan appropriately sized cuff with the bladder centered over the brachialartery.

Blood pressure should be recorded to the nearest 2 mmHg mark on themanometer or to the nearest whole number on an automatic device. A bloodpressure reading should be repeated 1 to 2 minutes later, and the secondreading should also be recorded to the nearest 2 mmHg mark.

Physical Examination

A physical examination must include source documentation of generalappearance, skin, and specific head and neck, heart, lung, abdomen,extremities, and neuromuscular assessments.

Height, Weight and Body Mass Index

Height and weight will be measured. Measurement of weight should beperformed with the patient dressed in indoor clothing, with shoesremoved, and bladder empty.

Waist Circumference

Waist circumference will be measured with a tape measure, as follows:Start at the top of the hip bone then bring the tape measure all the wayaround—level with the navel. Make sure the tape measure is snug, butwithout compressing the skin, and that it is parallel with the floor.

Patients should not hold their breath while measuring waistcircumference.

Electrocardiogram (ECG)

ECGs (standard 12-lead) will be obtained annually. Site personnel shouldmake every attempt to perform a patient's ECG using the same equipmentat each visit. ECGs will be reviewed by the site for the detection ofsilent MI. Silent MIs will be sent for event adjudication.

Treatment and Restrictions

Treatment

Treatment Regimen, Dosage, and Duration

Eligible study patients will be randomly assigned on Day 0 to one of the2 treatment groups. Patients in each group will receive either 4 g/dayAMR101 or placebo for up to 4.75 years (4 years planned median treatmentduration) according to Table 2.

The daily dose of study drug is 4 capsules per day taken as two capsulestake on two occasions per day (2 capsules given twice daily).

TABLE 2 Dosing Schedule during the Treatment Period Treatment GroupDaily Dose Number of Capsules per Day 1 4 g 4 capsules of 1000 mg AMR1012 Placebo 4 capsules of matching placebo

Patients will be instructed to take study drug with food (i.e., with orat the end of their morning and evening meals). On days that patientsare scheduled for study visits, the daily dose of study drug will beadministered by site personnel with food provided by the site followingcollection of all fasting blood samples. For the purposes of this study,fasting is defined as nothing by mouth except water (and any essentialmedications) for at least 10 hours.

Treatment Assignment

Identification Number

A unique patient identification number (patient number) will beestablished for each patient at each site. The patient number will beused to identify the patient throughout the study and will be entered onall documentation. If a patient is not eligible to receive treatment, orif a patient discontinues from the study, the patient number cannot bereassigned to another patient. The patient number will be used to assignpatients to one of the 2 treatment groups according to the randomizationschedule.

Drug Randomization

Only qualified patients who meet all of the inclusion criteria and noneof the exclusion criteria will be randomized and will receive studymedication starting at Visit 2 (Day 0). Eligible patients will berandomly assigned to one of the 2 treatment groups. Randomization willbe stratified by CV risk category, use of ezetimibe and by geographicalregion (Westernized, Eastern European, and Asia Pacific countries) (SeeSection 3.10). Approximately 70% of randomized patients will be in theCV Risk Category 1, including patients with established CVD, andapproximately 30% of randomized patients will be in the CV Risk Category2, including patients with diabetes and at least one additional riskfactor but no established CVD. Enrollment with patients of a CV riskcategory will be stopped when the planned number of patients in thatrisk category is reached.

Emergency Unblinding

In an emergency, when knowledge of the patient's treatment assignment isessential for the clinical management or welfare of the patient, theinvestigator may request the patient's treatment assignment forunblinding. Prior to unblinding the patient's individual treatmentassignment, the investigator should assess the relationship of anadverse event to the administration of the study drug (Yes or No). Ifthe blind is broken for any reason, the investigator must record thedate and reason for breaking the blind on the appropriate Case ReportForm (CRF) and source documents.

Compliance Control

It is recommended that, unless clear contraindications arise, patientsbe strongly encouraged to adhere to their treatment regimen with thestudy drug for the duration of the trial. Any interruptions of therapyshould, if possible, be brief (e.g., <4 weeks) and only for clinicallyindicated reasons, such as adverse events. Discontinuations will bediscouraged as much as possible. Any discontinuations should be based oncompelling clinical reasons.

For every patient, an assessment of compliance to the study drugtreatment regimen must be obtained at each scheduled visit. Studymedication will be dispensed in amounts exceeding the amount requiredfor the study. Patients will be instructed to return all unused studymedication at the next visit. Compliance to the study drug regimen willbe evaluated at each visit by counting unused capsules. Discrepancieswill be evaluated and discussed with each patient to assess compliance.If compliance is unsatisfactory, the patient will be counseled about theimportance of compliance to the dosing regimen. At the end of the study,the final study medication compliance will be determined by unusedcapsule count.

Study Restrictions

Concomitant Medications during Treatment/Follow-Up Period

Any medications administered during the study period must be documentedon the Concomitant Medication CRF. Patients must not have taken anyinvestigational agent within 90 days prior to screening. Patients cannotparticipate in any other investigational medication trial whileparticipating in this study.

The following non-study drug related, non-statin, lipid-alteringmedications and supplements, and foods are prohibited during the study(from Visit 1 until after the Last Visit-End of Study), except forcompelling medical reasons in ODIS patients:

niacin >200 mg/day;

fibrates;

prescription omega-3 fatty acid medications;

dietary supplements containing omega-3 fatty acids (e.g., flaxseed,fish, krill, or algal oils);

bile acid sequestrants;

cyclophosphamide;

systemic retinoids

If any of these products would be used during the treatment/follow-upperiod of the study, it should be for compelling medical reasons in ODISpatients, and it should be documented in the Concomitant Medication CRF.If the ODIS patient agrees to restart study medication, the use ofexcluded medication must be discontinued.

Foods enriched with omega-3 fatty acids are strongly discouraged afterVisit 1 for the duration of the study (does not apply to The Netherlandsor Canada only. Therefore, all centers in The Netherlands and Canadamust ignore this request).

The following products are allowed: statins, ezetimibe, and herbalproducts & dietary supplements not containing omega-3 fatty acids.

Statins:

The same statin at the same dose should be continued until the end ofthe study, unless deemed medically necessary to change because of anadverse event or lack of efficacy (LOE). It is preferred that if LOE isthe determining factor that ezetimibe be added to the present dose.

Switching between a brand name statin and the generic version of thesame statin is allowed at any time during the study.

Statins may be administered with or without ezetimibe.

Based on the FDA recommendation, simvastatin 80 mg be used only inpatients who have been taking this dose for 12 months or more and havenot experienced any muscle toxicity. (See reference: FDA Drug SafetyCommunication: Ongoing safety review of high-dose Zocor (simvastatin)and increased risk of muscle injury.(http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm204882.htm)

Changing of the type of statin or the statin dose during thetreatment/follow-up period of the study should only be done forcompelling medical reasons and must be documented in the CRF.

LDL-C Rescue:

If the level of LDL-C exceeds 130 mg/dL (3.37 mmol/L) during the study(initial measurement and confirmed by a second determination at least 1week later), the investigator may either increase the dose of thepresent statin therapy or may add ezetimibe to lower LDL-C. Theinvestigator should use the best clinical judgment for each patient.

No data are available with regard to potential interactions betweenethyl-EPA and oral contraceptives. There are no reports suggesting thatomega-3 fatty acids, including ethyl-EPA, would decrease the efficacy oforal contraceptives.

Patient Restrictions

Beginning at the screening visit, all patients should be instructed torefrain from excessive alcohol consumption, to follow a physicianrecommended diet and to maintain it through the duration of the study.Excessive alcohol consumption is on average 2 units of alcohol per dayor drinking 5 units or more for men or 4 units or more for women in anyone hour (episodic excessive drinking or binge drinking). A unit ofalcohol is defined as a 12-ounce (350 mL) beer, 5-ounce (150 mL) wine,or 1.5-ounce (45 mL) of 80-proof alcohol for drinks.

Investigational Product

Clinical Trial Material

The following will be supplied by the Sponsor:

AMR101 1000 mg capsules

Placebo capsules

The Sponsor will supply sufficient quantities of AMR101 1000 mg capsulesand placebo capsules to allow for completion of the study. The lotnumbers of the drugs supplied will be recorded in the final studyreport.

Records will be maintained indicating the receipt and dispensation ofall drug supplies. At the conclusion of the study, any unused study drugwill be destroyed.

Pharmaceutical Formulations

AMR101 1000 mg and placebo capsules (paraffin) are provided inliquid-filled, oblong, gelatin capsules. Each capsule is filled with aclear liquid (colorless to pale yellow in color). The capsules areapproximately 25.5 mm in length with a diameter of approximately 9.5 mm.

Labeling and Packaging

Study medication will be packaged in high-density polyethylene bottles.Labeling and packaging will be performed according to GMP guidelines andall applicable country-specific requirements. The bottles will benumbered for each patient based on the randomization schedule. Thepatient randomization number assigned by IWR or a designee of theSponsor for the study (if no IWR system is used), will correspond to thenumber on the bottles. The bottle number for each patient will berecorded in the Electronic Data Capture (EDC) system for the study.

Dispensing Procedures and Storage Conditions

Dispensing Procedures

At Visit 2 (Day 0), patients will be assigned study drug according totheir treatment group determined by the randomization schedule. Onceassigned to a treatment group, patients will receive study drugsupplies. At each visit, patients will bring unused drug suppliesdispensed to them earlier. From the drug supplies assigned to eachpatient, site personnel will administer drug while the patients are atthe Research Site.

The investigator or designee must contact the IWR system or a designeeof the Sponsor for the study (if no IWR system is used) when anyunscheduled replacements of study medication are needed.

During the last visit during the treatment period, patients will bringthe unused drug supplies for site personnel to calculate the final studymedication compliance by unused capsule count.

Storage Conditions

At the Research Sites, study drugs must be stored at room temperature,68° F. to 77° F. (20° C. to 25° C.). Do not allow storage temperature togo below 59° F. (15° C.) or above 86° F. (30° C.). Store in the originalpackage.

Study drugs must be stored in a pharmacy or locked and secure storagefacility, accessible only to those individuals authorized by theinvestigator to dispense the drug. The investigator or designee willkeep accurate dispensing records. At the conclusion of the study, studysite personnel will account for all used and unused study drug. Anyunused study drug will be destroyed. The investigator agrees not todistribute study drug to any patient, except those patientsparticipating in the study.

Efficacy Assessments

Specification of Variables and Procedures

The primary endpoint and the majority of the secondary and tertiaryendpoints are based on clinical events related to CVD and mortality. Allevents occurring between randomization and the study end date(inclusive) must be recorded. Only adjudicated events will be includedin the final analyses. Further details on the assessment of clinicalevents and their definitions will be found in the CEC charter.

Efficacy Endpoints

Primary Efficacy Endpoint

Time from randomization to the first occurrence of the composite of thefollowing clinical events:

CV death,

Nonfatal MI (including silent MI; ECGs will be performed annually forthe detection of silent MIs),

Nonfatal stroke,

Coronary revascularization

Hospitalization for unstable angina determined to be caused bymyocardial ischemia by invasive/non-invasive testing.

The first occurrence of any of these major adverse vascular eventsduring the follow-up period of the study will be included in theincidence.

Secondary Efficacy Endpoints

The key secondary efficacy endpoint is:

The composite of death from CV causes, nonfatal MI, coronaryrevascularization, unstable angina determined to be caused by myocardialischemia by invasive/non-invasive testing and requiring emergenthospitalization, nonfatal stroke, or peripheral CVD requiringintervention, angioplasty, bypass surgery, or aneurysm repair.

Other secondary efficacy endpoints are as follows (to be tested in saidorder):

The composite of total mortality, nonfatal MI, or nonfatal stroke;

The composite of death from CV causes, nonfatal MI, coronaryrevascularization, unstable angina determined to be caused by myocardialischemia by invasive/non-invasive testing and requiring emergenthospitalization, peripheral CVD requiring intervention, or cardiacarrhythmia requiring hospitalization;

The composite of death from CV causes, nonfatal MI, coronaryrevascularization, or unstable angina determined to be caused bymyocardial ischemia by invasive/non-invasive testing and requiringemergent hospitalization;

The composite of death from CV causes or nonfatal MI;

Total mortality;

Fatal and nonfatal MI (including silent MI);

Coronary Revascularization;

Hospitalization for unstable angina determined to be caused bymyocardial ischemia by invasive/non-invasive testing;

Fatal and nonfatal stroke.

For the secondary endpoints that count a single event, the firstoccurrence of this type of event will be counted in each patient. Forsecondary endpoints that are composites of two or more types of events,the first occurrence of any of the event types included in the compositewill be counted in each patient.

Tertiary Efficacy Endpoints:

The second, third, fourth, and fifth major CV event of the primarycomposite endpoint. The type of (nonfatal) events may occur in anyorder.

Primary endpoint in subset of patients with diabetes mellitus;

Primary endpoint in subset of patients with metabolic syndrome;

New CHF, new CHF leading to hospitalization, transient ischemic attack,amputation for CVD and carotid revascularization;

Elective coronary revascularization and emergent coronaryrevascularization;

New onset diabetes;

Fasting TG, TC, LDL-C, HDL-C, non-HDL-C, VLDL-C, apo B, hs-CRP, andhsTnT: effect of baseline and on-treatment change of biomarkers onprimary and key secondary endpoints;

CV mortality;

Cardiac Arrhythmias requiring hospitalization;

Cardiac Arrest;

To explore the effect of AMR101 on weight and waist circumference.

For the tertiary endpoints that count a single event, the firstoccurrence of this type of event will be counted in each patient. Fortertiary endpoints that are composites of two or more types of events,the first occurrence of any of the event types included in the compositewill be counted in each patient (except when stated otherwise, for thesecond, third, fourth, and fifth major CV event).

Safety Assessments

Specification of Variables and Procedures

Safety assessments will include adverse events, clinical laboratorymeasurements (chemistry, hematology), 12-lead ECGs, vital signs(systolic and diastolic blood pressure, heart rate, respiratory rate,and body temperature), and physical examinations as per StudyProcedures/Table 1.

A complete medical, surgical and family history will be completed atVisit 1.

All laboratory test results must be evaluated by the investigator as totheir clinical significance. Any observations at physical examinationsor laboratory values considered by the investigator to be clinicallysignificant should be considered an adverse event.

Adverse Events

An adverse event is defined as any untoward medical occurrence, whichdoes not necessarily have a causal relationship with the medicationunder investigation. An adverse event can therefore be any unfavorableand/or unintended sign (including an abnormal laboratory finding),symptom, or disease temporally associated with the use of aninvestigational medication product, whether or not related to theinvestigational medication product. All adverse events, includingobserved or volunteered problems, complaints, or symptoms, are to berecorded on the appropriate CRF. Each adverse event is to be evaluatedfor duration, intensity, and causal relationship with the studymedication or other factors.

Adverse events, which include clinical laboratory test variables, willbe monitored from the time of informed consent until study participationis complete. Patients should be instructed to report any adverse eventthat they experience to the investigator. Beginning with Visit 2,investigators should assess for adverse events at each visit and recordthe event on the appropriate adverse event CRF.

Wherever possible, a specific disease or syndrome rather than individualassociated signs and symptoms should be identified by the investigatorand recorded on the CRF. However, if an observed or reported sign orsymptom is not considered a component of a specific disease or syndromeby the investigator, it should be recorded as a separate adverse eventon the CRF.

Any medical condition that is present when a patient is screened orpresent at baseline that does not deteriorate should not be reported asan adverse event. However, medical conditions or signs or symptomspresent at baseline and that change in severity or seriousness at anytime during the study should be reported as an adverse event.

Clinically significant abnormal laboratory findings or other abnormalassessments that are detected during the study or are present atbaseline and significantly worsen will be reported as adverse events orSAEs. The investigator will exercise his or her medical and scientificjudgment in deciding whether an abnormal laboratory finding or otherabnormal assessment is clinically significant.

The investigator will rate the severity (intensity) of each adverseevent as mild, moderate, or severe, and will also categorize eachadverse event as to its potential relationship to study drug using thecategories of Yes or No.

Severity:

Mild—An event that is usually transient in nature and generally notinterfering with normal activities.

Moderate—An event that is sufficiently discomforting to interfere withnormal activities.

Severe—An event that is incapacitating with inability to work or dousual activity or inability to work or perform normal daily activity.

Causality Assessment:

The relationship of an adverse event to the administration of the studydrug is to be assessed according to the following definitions:

No (unrelated, not related, no relation)—The time course between theadministration of study drug and the occurrence or worsening of theadverse event rules out a causal relationship and another cause(concomitant drugs, therapies, complications, etc.) is suspected.

Yes—The time course between the administration of study drug and theoccurrence or worsening of the adverse event is consistent with a causalrelationship and no other cause (concomitant drugs, therapies,complications, etc.) can be identified.

The following factors should also be considered:

The temporal sequence from study medication administration

The event should occur after the study medication is given. The lengthof time from study medication exposure to event should be evaluated inthe clinical context of the event.

Underlying, concomitant, intercurrent diseases

Each report should be evaluated in the context of the natural historyand course of the disease being treated and any other disease thepatient may have.

Concomitant medication

The other medications the patient is taking or the treatment the patientreceives should be examined to determine whether any of them might berecognized to cause the event in question.

Known response pattern for this class of study medication

Clinical and/or preclinical data may indicate whether a particularresponse is likely to be a class effect.

Exposure to physical and/or mental stresses

The exposure to stress might induce adverse changes in the patient andprovide a logical and better explanation for the event.

The pharmacology and pharmacokinetics of the study medication

The known pharmacologic properties (absorption, distribution,metabolism, and excretion) of the study medication should be considered.

Unexpected Adverse Events—An unexpected adverse event is an adverseevent either not previously reported or where the nature, seriousness,severity, or outcome is not consistent with the current Investigator'sBrochure.

Serious Adverse Events

A serious adverse event (SAE) is defined as an adverse event that meetsany of the following criteria:

Results in death

Is life-threatening—Note: The term “life-threatening” in the definitionof “serious” refers to an event in which the patient was at risk ofdeath at the time of the event. It does not refer to an event, whichhypothetically might have caused death, if it were more severe.

Requires hospitalization or prolongation of existinghospitalization—Note: In general, hospitalization for treatment of apre-existing condition(s) that did not worsen from baseline is notconsidered adverse events and should not be reported as SAEs.

Results in disability/incapacity

Is a congenital anomaly/birth defect;

Is an important medical event—Note: Important medical events that maynot result in death, be life threatening, or require hospitalization maybe considered an SAE when, based upon appropriate medical judgment, theymay jeopardize the patient and may require medical or surgicalintervention to prevent one of the outcomes listed above. Examples ofsuch medical events include allergic bronchospasm requiring intensivetreatment in an emergency room or at home, blood dyscrasias orconvulsions that do not result in inpatient hospitalizations, or thedevelopment of drug dependency.

By design of this study SAEs that are endpoint events will only berecorded for the endpoint determination and not captured as SAEs. Theintention is that the endpoint events are not reported to IRBs as SAEs,unless the IRB requires that these are reported. Investigators shouldspecifically inform their institution/IRB of this plan and confirmwhether or not they want the endpoint events reported. By agreement withthe US FDA, these endpoints will also not be reported to the US FDA asSAEs; rather they will be reported as endpoint events. Followingadjudication if the event is determined to not meet the criteria for anevent, the event will be evaluated as an SAE beginning with that day asDay 0.

Serious Adverse Event Reporting—Procedure for Investigators

Initial Reports

All SAEs occurring from the time of informed consent until 28 daysfollowing the last administration of study medication must be reportedto the Sponsor or designee within 24 hours of the knowledge of theoccurrence (this refers to any adverse event that meets any of theaforementioned serious criteria). SAEs that the investigator considersrelated to study medication occurring after the 28-day follow-up periodwill also be reported to the Sponsor or designee.

The investigator is required to submit SAE reports to the InstitutionalReview Board (IRB) or Independent Ethics Committee (IEC) in accordancewith local requirements. All investigators involved in studies using thesame investigational medicinal product (IMP) will receive any SuspectedUnexpected Serious Adverse Reaction (SUSAR) reports for onwardsubmission to their local IRB as required. All reports sent toinvestigators will be blinded.

In addition, regulatory agencies will be notified of SAEs per therequirements of the specific regulatory jurisdiction regulations andlaws.

Follow-Up Reports

The investigator must continue to follow the patient until the SAE hassubsided, or until the condition becomes chronic in nature, stabilizes(in the case of persistent impairment), or the patient dies. Within 24hours of receipt of follow-up information, the investigator must updatethe SAE form electronically in the EDC system for the study and submitany supporting documentation (e.g., laboratory test reports, patientdischarge summary, or autopsy reports) to the Sponsor or designee viafax or email.

Reporting by the Sponsor

IRBs and IECs will be informed of SUSARs according to localrequirements. Cases will be unblinded for reporting purposes asrequired.

Exposure In Utero During Clinical Trials

If a patient becomes pregnant during the study, the investigator shouldreport the pregnancy to the Sponsor or designee within 24 hours of beingnotified. The Sponsor or designee will then forward the Exposure InUtero form to the investigator for completion.

The patient should be followed by the investigator until completion ofthe pregnancy. If the pregnancy ends for any reason before theanticipated date, the investigator should notify the Sponsor ordesignee. At the completion of the pregnancy, the investigator willdocument the outcome of the pregnancy. If the outcome of the pregnancymeets the criteria for immediate classification as an SAE (i.e.,postpartum complication, spontaneous abortion, stillbirth, neonataldeath, or congenital anomaly), the investigator should follow theprocedures for reporting an SAE.

Treatment Discontinuation/Patient Withdrawal

Patients may withdraw from the study at any time and for any reason.Study drug administration may also be discontinued at any time, at thediscretion of the investigator. In any case, follow-up for efficacy andsafety should be continued.

Reasons for Early Study Drug Discontinuation

Study drug discontinuation should be avoided as much as possible, butmay be done for any of the following reasons:

Patient withdraws consent or requests early discontinuation from thestudy for any reason. Patients should be encouraged to continue toparticipate in the study for the entire duration of the study even ifthey choose not to take study medication any longer.

Occurrence of a clinical or laboratory adverse event, either serious ornon-serious, at the discretion of the investigator. The Sponsor ordesignee should be notified if a patient is discontinued because of anadverse event or laboratory abnormality. It is recommended that, unlessclear contraindications arise, patients be strongly encouraged to adhereto their treatment regimen with the study drug for the duration of thetrial. Any interruptions of therapy should, if possible, be brief (e.g.,<4 weeks) and only for clinically indicated reasons, such as adverseevents. The following should be considered reason for discontinuation:

ALT >3×ULN and bilirubin >1.5×ULN

ALT >5×ULN

ALT >3×ULN and appearance or worsening of hepatitis

ALT >3×ULN persisting for >4 weeks

ALT >3×ULN and cannot be monitored weekly for 4 weeks

Any medical condition or personal circumstance that, in the opinion ofthe investigator, exposes the patient to risk by continuing in the studyor precludes adherence to the protocol.

Sponsor discontinues the study.

A TG value that is flagged as critically high, i.e., >1000 mg/dL (11.29mmol/L), and confirmed as critically high by a repeat measurement (newfasting blood sample) within 7 days. In this case, a patient may bediscontinued from study drug (with the option to remain ODIS) and otherlipid-altering medications may be (re)initiated. If the TG value isflagged as >2000 mg/dL (22.58 mmol/L) then appropriate medical actioncan be taken by the investigator as soon as possible.

Occurrence of an outcome event according to the judgment of theinvestigator is not considered a valid reason for study drugdiscontinuation.

Patients whose treatment with study medication is discontinued early,and have not withdrawn consent, will stay in study and will be monitoreduntil the end of the study. Patients that continue in the study afterindefinite cessation of therapy will be characterized as Off Drug InStudy (ODIS). ODIS patients should be asked to return to the study sitefor an interim visit once the patient has been off study drug for >30days. Procedures at this visit are consistent with those at Visit 5. Ifnot contraindicated, patients will also have the option to restart studymedication at any point once characterized as ODIS.

The reason for study drug discontinuation or interruption will berecorded on the CRF.

Follow-Up after Early Study Drug Discontinuation/Lost to Follow-Up

Patients who prematurely discontinue study drug are not to be replaced.

All randomized patients must be followed up according to the studyflowchart until the study end date or death, regardless of whether theydiscontinue study drug prematurely or not. Any event occurring afterearly study drug discontinuation will be recorded up through the studyend date.

In order to follow the medical status of the patients, especially whenthey discontinued the study, investigators are encouraged to obtaininformation from the patient's primary care practitioner (physician orany other medical care provider). Investigators are also requested totry as much as possible to re-contact those patients at the end of thetrial to obtain at least their vital status as well as their status withrespect to the primary endpoint, and thus avoid lost to follow-up forthe efficacy assessment.

If patients are lost to follow-up, the CRF must be completed up to thelast visit or contact.

Statistics

Analysis Populations

Randomized Population

The randomized population will include all patients who sign theinformed consent form and are assigned a randomization number at Visit 2(Day 0).

Intent-to-Treat Population

The Intent-to-Treat (ITT) population will consist of all randomizedpatients who take at least one dose of study drug. The ITT population isthe primary analysis population. All efficacy analyses will be performedon the ITT population.

Per-Protocol Population

The per-protocol (PP) population will include all ITT patients withoutany major protocol deviations, and who had ≥80% compliance with studydrug while on treatment (up to discontinuation for patients whosetreatment is terminated early). The per-protocol efficacy analysis forCV events will be restricted to each patient's time on study drug plus30 days thereafter.

Safety Population

All safety analyses will be conducted based on the safety population,which is defined as all randomized patients who receive at least onedose of study drug. This is the same as the ITT population.

Statistical Methods

Safety and efficacy variables will be analyzed using appropriatestatistical methods to be described in detail in a separate StatisticalAnalysis Plan (SAP). The SAP will be finalized before study unblinding.

Patient Disposition and Demographic/Baseline Characteristics

The numbers of patients screened, the number of patients randomized pertreatment group (randomized population), and the number of patients inthe ITT and PP populations by treatment group will be listed.

For randomized patients who discontinued treatment with study drug, theprimary reason for discontinuation will be listed and summarized bytreatment group.

Summary statistics (mean, standard deviation, median, minimum andmaximum) will be provided by treatment group for demographiccharacteristics (e.g., age, sex, race, and ethnicity) and baselinecharacteristics (e.g., body weight, height, and body mass index) in theITT and PP populations.

Demographic data and baseline characteristics will be compared amongtreatment groups for the ITT and PP population. Differences indemographic and baseline characteristics will be tested using achi-square test (for categorical variables) or a 1-way analysis ofvariance model with treatment as a factor (for continuous variables).The p-values will be used as descriptive statistics, primarily as anassessment of the adequacy of randomization.

Study Medication Exposure and Compliance

The final compliance to study drug will be calculated as the percent ofdoses taken relative to doses scheduled to be taken. Overall percentcompliance will be calculated per patient in the ITT and PP populationsand summarized by treatment group using summary statistics (n, mean,standard deviation, median, minimum, and maximum).

Concomitant Therapies

Concomitant medication/therapy verbatim terms will be coded using thelatest version of the World Health Organization Drug Dictionary. Thenumbers and percentages of patients in each treatment group takingconcomitant medications will be summarized by anatomic and therapeuticchemical classification and preferred term.

Analysis of Efficacy

For efficacy endpoints including CV events, only adjudicated events willbe included in the final statistical analyses.

Summary Statistics

Summary statistics (n, mean, standard deviation, median, minimum, andmaximum) for the baseline and post-baseline measurements, the percentchanges, or changes from baseline will be presented by treatment groupand by visit for all efficacy variables to be analyzed. The summarystatistics will include changes in body weight and body mass index frombaseline by treatment group and by visit.

Primary Endpoint

The primary efficacy endpoint is the time from randomization to thefirst occurrence of any component of the composite of the followingclinical events:

CV death,

Nonfatal MI (including silent MI),

Nonfatal stroke,

Coronary revascularization,

Hospitalization for unstable angina determined to be caused bymyocardial ischemia by invasive/non-invasive testing.

The analysis of the primary efficacy endpoint will be performed usingthe log-rank test comparing the 2 treatment groups (AMR101 and placebo)and including the stratification factor “CV risk category”, use ofezetimibe and geographical region (Westernized, Eastern European, andAsia Pacific countries) (each as recorded in the IWR at the time ofenrollment) as covariates. Treatment difference will be tested at alphalevel of 0.0476 accounting for one interim efficacy analysis. The hazardratio for treatment group (AMR101 vs. placebo) from a Cox proportionalhazard model that includes the stratification factor will also bereported, along with the associated 95% confidence interval.Kaplan-Meier estimates from randomization to the time to the primaryefficacy endpoint will be plotted.

The size and direction of the treatment effects of the individualcomponents of the composite endpoint and their relative contribution tothe composite endpoint will be determined as well.

Secondary Endpoints

The statistical analyses of the secondary endpoints will be analyzed bythe same log-rank test specified above for the primary efficacyendpoint. Treatment differences will be tested at alpha level of 0.05using a sequential procedure for controlling type 1 error starting withthe key secondary variable. The remaining secondary variables will betested in the order specified in Section 9.2.2. Estimates of the hazardratios from the Cox proportional hazard model and the associated 95%confidence intervals will also be provided. Kaplan-Meier estimates fromrandomization the time to the secondary efficacy endpoints will beplotted.

Tertiary Endpoints

For event rates, the statistical analyses of the tertiary endpoints willbe similar to the analysis of the secondary efficacy endpoints. Alltertiary analyses will be conducted for the ITT population. Noadjustments for multiple testing will be made.

For measurements of lipids, lipoproteins and inflammatory markers thechange from baseline will be analyzed in the units of each marker, andthe percent change from baseline. Since these biomarkers are typicallynot normally distributed, the Wilcoxon rank-sum test will be used fortreatment comparisons of the percent change from baseline, and mediansand quartiles will be provided for each treatment group. The medians ofthe differences between the treatment groups and 95% confidenceintervals will be estimated with the Hodges-Lehmann method.

New onset diabetes is defined as Type 2 diabetes newly diagnosed duringthe treatment/follow-up period (i.e. patients with no history ofdiabetes at randomization).

For purposes of this study, a diagnosis of diabetes is made based on theobservation of:

1. HbA_(1c)≥6.5%. The test should be performed in a laboratory using amethod that is National Glycohemoglobin Standardization Program (NGSP)certified and standardized to the Diabetes Control and ComplicationsTrial (DCCT) assay. In the absence of unequivocal hyperglycemia,HbA_(1c)≥6.5% should be confirmed by repeat testing.

OR

2. Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L). Fasting isdefined as no caloric intake for at least 8 hr. In the absence ofunequivocal hyperglycemia, FPG ≥126 mg/dL (7.0 mmol/L) should beconfirmed by repeat testing.

OR

3. 2-hr plasma glucose ≥200 mg/dL (11.1 mmol/L) during an Oral GlucoseTolerance Test (OGTT). The test should be performed as described by theWorld Health Organization, using a glucose load containing theequivalent of 75 g anhydrous glucose dissolved in water. In the absenceof unequivocal hyperglycemia, 2-hr plasma glucose ≥200 mg/dL (11.1mmol/L) during an Oral Glucose Tolerance Test (OGTT) should be confirmedby repeat testing.

OR

4. In a patient with classic symptoms of hyperglycemia or hyperglycemiccrisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L).

Exploratory Subgroup Analyses

Subgroup analyses of the primary and key secondary endpoints (as definedin the Statistical Analysis Plan) will be performed. All subgroupanalyses will be conducted for the ITT population. No adjustments formultiple testing will be made.

Log-rank tests, treatment effects and the associated 95% confidenceintervals for the primary and key secondary efficacy endpoints withineach subgroup will be provided using the Cox proportional hazard modelwith treatment (AMR101 or placebo), and stratification as a factor (withthe exception of the subgroup analyses of those subgroup variablesrelated to the stratification factors, i.e., CV risk category that willnot have stratification as a factor).

Subgroups including, but not limited to the following, will be explored.A complete list will be prospectively defined in the StatisticalAnalysis Plan.

Demographics:

Gender,

age (<65 yr and ≥65 yr),

race (white and nonwhite, or any other subset with at least 10% of thetotal number of patients),

geography (western vs. non-western)

Disease Parameters:

CV risk category,

the presence/absence of diabetes at baseline,

renal impairment

Treatment Parameters:

by statin intensity (statin type and regimen),

relevant concomitant medications,

Baseline Lipid and Lipoprotein Parameters:

LDL-C (by tertile),

HDL-C (by tertile),

TG (by tertile),

TG ≥150 mg/dL,

TG ≥200 mg/dL and TG <200 mg/dL, combined highest tertile for TG andlowest tertile for HDL-C,

hs-CRP (≤3 mg/L and >3 mg/L),

Apo B (by tertile),

non-HDL-C (by tertile)

The consistency of the treatment effects in subgroups will be assessedfor the primary and key secondary efficacy endpoints. For each subgroupvariable, a Cox proportional hazard model with terms for treatment,stratification factors (with the exception of those subgroup variablesrelated to the stratification factors, i.e., CV risk category),subgroup, and treatment-by-subgroup interaction will be performed. Themain treatment effect will not be tested with this model. P-values fortesting the interaction terms will be provided.

Interim Efficacy Analysis

One interim analysis will be performed for the primary efficacy endpointusing best available data (adjudicated events and site reportedendpoints) based on data when approximately 60% of the total number ofprimary endpoint events is reached. The interim analysis will be basedon a group sequential design that includes early stopping rules forbenefit while preserving the overall Type I error rate(O'Brien-Fleming). This allows for interim analysis and preserves theoverall Type I error probability of α=0.05 for the primary endpoint.

Approximately 1612 primary efficacy endpoint events are planned to beobserved during the trial, based on sample size calculation assumptions.Therefore, the interim analysis will occur after at least 967 primaryefficacy endpoint events have been observed. According to this boundary,the critical p-value at the interim analysis has to be p≤0.0076,resulting in the final evaluation p-value of 0.0476.

The interim results of the study will be monitored by an independentDMC. The analyses will be performed by the independent statistical groupunblinded to the treatment assignment. The results will be reported onlyto the DMC. The unblinded information will not be released to sponsorunder any circumstance before the completion of the study. Specificstatistical guidelines for data monitoring will be discussed andformalized in a separate Interim Statistical Analysis Plan and DMCCharter.

Analysis of Safety

All analyses of safety will be conducted on the safety population, whichis defined as all randomized patients who receive at least one dose ofstudy drug. The safety assessment will be based on the frequency ofadverse events, physical exams, vital signs and safety laboratory tests.

Adverse events with new onset during the study between the initiation ofstudy drug and 30 days after the last dose of study drug for eachpatient will be considered treatment-emergent (TEAEs). This will includeany AE with onset prior to initiation of study drug and increasedseverity after the treatment initiation.

Treatment-emergent adverse events will be summarized by system organclass and preferred term, and by treatment. This will include overallincidence rates (regardless of severity and relationship to study drug),and incidence rates for moderate or severe adverse events. A summary ofSAEs and adverse events leading to early discontinuation from the studywill be presented through data listings.

Safety laboratory tests and vital signs will be summarized bypost-treatment change from baseline for each of the parameters usingdescriptive statistics by treatment group. Those patients withsignificant laboratory abnormalities will be identified in datalistings. Additional safety parameters will be summarized in datalistings.

Sample Size Determination

Sample size estimation is based on the assumption that the primarycomposite endpoint (time from randomization to the first occurrence ofCV death, non-fatal MI, non-fatal stroke, coronary revascularization, orunstable angina requiring hospitalization) would be relatively reducedby 15%, from an event rate by 4 years of 23.6% in the placebo group to20.5% in the AMR101 group. It is expected that a minimum of 1612 primaryefficacy endpoint events will be required during the study. A total ofapproximately 6990 patients are needed to be able to detect thisdifference at 4.76% significance level (because of the interim analysisdescribed in Section 12.2.4.6) and with 90% power, assuming an 18-monthenrollment period and a median follow-up of 4 years. The current samplesize calculation is based on an estimated placebo yearly event rate of5.9% (23.6% over 4 years). To protect against the possibility that theactual placebo event rate is lower than estimated, an extra 1000patients will be enrolled (approximately 7990 patients in total). Byadding the extra 1000 patients, the event rate in the placebo groupcould be 5.2% per year (20.8% over 4 years) without having to modify theother sample size assumptions.

Since this is an events-driven trial, the ‘sample size’ is the number ofevents rather than the number of patients. The number of events thatoccur depends primarily on three factors: how many patients areenrolled, the combined group event rate, and how long the patients arefollowed. Because of the difficulty in predicting the combined eventrate, the sponsor will monitor that event rate as the trial progresses.If the combined event rate is less than anticipated, either increasingthe number of patients, extending the length of follow-up, or a balanceof adjusting both factors may be necessary to achieve the sample size of1612 events.

Before completing the enrollment phase of the trial, i.e. approximately3- to 6-months prior to the projected enrollment of the 7990th patient,the actual event rate based on pooled, blinded accumulation of primaryefficacy endpoint events will be calculated and plotted. If thoseanalyses suggest the number of patients with at least 1 adjudicated,primary event (and appropriately accounting for patients with potentialprimary events for which the adjudication process is then incomplete) isconsistent with projections, then the study could continue toward theprotocol-specified target enrollment of 7990 patients. However, if thenumber of such events appears less than, and inconsistent withprojections, the Sponsor will consider (under blinded conditions)re-calculating the number of patients needed to achieve the targetnumber of events within the desired timeline or extend the follow-upperiod. If the projected increase in number of patients is ≤25% of theoriginal 7990 target population, the Sponsor may, with documentedapproval of both the REDUCE-IT Steering Committee (SC) and the DataMonitoring Committee (DMC), extend enrollment to the revised targetnumber without need for an additional protocol amendment. Under thoseconditions, all principal investigators, ethics committees, andregulatory authorities associated with the protocol will be promptlynotified of the action. Should the projected increase in number ofpatients be more than 25% above the original 7990 target (i.e. more than1998 additional patients) a formal protocol amendment will be initiated.

If the number of patients to be studied is increased, the enrollmentphase will be extended to allow enrollment of the additional patients.

At completion of study enrollment, the actual number of patientsrandomized may vary from the target number (either original or revised)as a result of the inherent lag between the date the last patientstarted screening and the date the last patient was randomized.

Monitoring, Data Management, and Record Keeping

Data Management

Data Handling

Data will be recorded at the site on CRFs. All entries on a CRF areultimately the responsibility of the Investigator, who is expected toreview each form for completeness and accuracy before signing. A CRFmust be completed for each randomized patient. The CRFs and sourcedocuments must be made available to the Sponsor and/or its designee.

Record Keeping

The Investigator must maintain all documents and records, originals orcertified copies of original records, relating to the conduct of thistrial, and necessary for the evaluation and reconstruction of theclinical trial. This documentation includes, but is not limited toprotocol, CRFs, AE reports, patient source data (including records ofpatients, patient visit logs, clinical observations and findings),correspondence with health authorities and IRB, consent forms, inventoryof study product, Investigator's curriculum vitae, monitor visit logs,laboratory reference ranges and laboratory certification or qualitycontrol procedures, and laboratory director curriculum vitae.

The Investigator and affiliated institution should maintain the trialdocuments as required by the applicable regulations. The Investigatorand affiliated institution should take measures to prevent accidental orpremature destruction of documents. Clinical trial documents must bekept in the clinical site's archives indefinitely, unless writtenauthorization is obtained from the Sponsor.

Direct Access to Source Data/Documents

The investigator and research institution agree that the Sponsor, theirrepresentatives and designees, the IRB or IEC, and representatives fromworldwide regulatory agencies will have the right, both during and afterthe clinical trial, to review and inspect pertinent medical recordsrelated to the clinical trial.

Quality Control and Quality Assurance

The Sponsor and/or its designee(s) will perform quality control andquality assurance checks of all clinical trials that it sponsors. Beforethe enrollment of any patient in this study, the Sponsor or its designeewill review with the investigator and site personnel the followingdocuments: protocol, Investigator's Brochure, CRFs and procedures fortheir completion, the informed consent process, and the procedure forreporting SAEs. Site visits will be performed by the Sponsor and/or itsdesignees. During these visits, information recorded on the CRFs will beverified against source documents and requests for clarification orcorrection may be made. After the CRF data is entered by the site, theSponsor or designee will review for safety information, completeness,accuracy, and logical consistency. Computer programs that identify datainconsistencies may be used to help monitor the clinical trial. Ifnecessary, requests for clarification or correction will be sent toinvestigators.

By signing the protocol, the Sponsor agrees directly or through itsdesignee(s) to be responsible for implementing and maintaining qualitycontrol and quality assurance systems with written standard operatingprocedures to ensure that trials are conducted and data are generated,documented, and reported in compliance with the protocol, acceptedstandards of Good Clinical Practice (GCP), International Conference onHarmonization (ICH) and other applicable regulations.

Completion of Study

The end of the study will be at the time of the last patient-last visitof the follow-up period of the study. The IRB and IEC will be notifiedabout the end of the study according to country-specific regulatoryrequirements.

TABLE 1 SCHEDULE OF PROCEDURES Screening If a Visit 1.1 Up to takesplace, 42 Visit 1 may days occur up before to 60 days Follow-Up (FU)¹³Study Day Day 0 before Day 0² 0 120 ± 10 360 ± 10 720 ± 10 1080 ± 101440 ± 10 1800 + 30 Months of FU 0 4 12 24 36 48 60 Years of FU 0 0.33 12 3 4 5 Visit # 1 1.1 2 3 4 5 6 7 LV¹⁴ Study Procedures: Informed XConsent Medical, X Surgical & Family History Demographics X Evaluate  X¹ X³ X inclusion/ exclusion criteria Physical X X X X X X X ExaminationWeight, Height⁴ X X X X X X X X Vital Signs⁵ X X X X X X X X X Waist X XX Circumference 12-Lead ECG X X X X X X X Urine X X pregnancy test⁶Concomitant X X X X X X X X X Meds Randomization X Dosing X X X X X X atthe Research Site⁷ Efficacy events X X X X X X AE Evaluations X X X X XX X Compliance X X X X X X Check⁸ Chemistry and X  X³ X X X X X X Xhematology⁹ Fasting lipid X  X³ X X X X X X X profile¹⁰ Genetictesting¹¹ X Biomarkers: hs- X X X CRP, apo B, hsTNT Fasting blood X X XX X X sample for archiving¹²

What is claimed is:
 1. A method of reducing risk of a cardiovascularevent in a subject on statin therapy with residual atherogenicdyslipidemia and clinically evident cardiovascular disease, the methodcomprising administering to the subject about 2 g to about 4 g of apharmaceutical composition comprising eicosapentaenoic acid anddocosapentaenoic acid per day for a period of at least about 2 years,wherein said administration reduces risk of cardiovascular death, riskof unstable angina and/or need for coronary revascularization.
 2. Themethod of claim 1, wherein the composition is administered to thesubject in 1 to 4 dosage units per day.
 3. The method of claim 1,wherein the eicosapentaenoic acid comprises at least about 90 wt. % ofall omega-3 fatty acids in the pharmaceutical composition.
 4. The methodof claim 1, wherein the eicosapentaenoic acid comprises at least about96 wt. % of all omega-3 fatty acids in the pharmaceutical composition.5. The method of claim 1, wherein the docosapentaenoic acid comprisesless than 10 wt. % of all omega-3 fatty acids in the pharmaceuticalcomposition.
 6. The method of claim 1, wherein the docosapentaenoic acidcomprises less than 8 wt. % of all omega-3 fatty acids in thepharmaceutical composition.
 7. The method of claim 1, wherein thedocosapentaenoic acid comprises less than 5 wt. % of all omega-3 fattyacids in the pharmaceutical composition.
 8. The method of claim 1,wherein the pharmaceutical composition further comprises less than 5%docosahexaenoic acid, by weight, of all omega-3 fatty acids in thepharmaceutical composition.
 9. The method of claim 1 further comprisinga step of measuring the subject's baseline lipid profile prior toadministering the pharmaceutical composition to the subject.
 10. Themethod of claim 1, wherein the subject has one or more of: a baselinenon-HDL-C value of about 200 mg/dL to about 300 mg/dL; a baseline totalcholesterol value of about 250 mg/dL to about 300 mg/dL; a baselineVLDL-C value of about 140 mg/dL to about 200 mg/dL; a baseline HDL-Cvalue of about 10 to about 30 mg/dL; and/or a baseline LDL-C value ofabout 40 to about 100 mg/dL.
 11. The method of claim 1, wherein thestatin therapy comprises administering to the subject a statin andoptionally ezetimibe.
 12. The method of claim 1, wherein the subject:(a) has not been administered 200 mg or more per day of niacin and/orfibrates for at least 28 days before administration of thepharmaceutical composition; (b) has not been administered omega-3 fattyacid prescription for a period of time beginning 28 days prior toadministration of the pharmaceutical composition; or (c) has notingested dietary supplements comprising omega-3 fatty acids for a periodof time beginning 28 days prior to administration of the pharmaceuticalcomposition.
 13. The method of claim 1, wherein the subject isadministered about 3 g or about 4 g of the pharmaceutical compositionper day for at least about 3 years.
 14. The method of claim 1, whereinthe pharmaceutical composition is formulated to delay onset of a firstsaid cardiovascular event of said subject compared with controlsubjects, wherein each said control subject is on stable statin therapy,has a fasting baseline triglyceride level of about 135 mg/dL to about500 mg/dL, and has established cardiovascular disease.
 15. The method ofclaim 14, wherein the medicament is formulated to delay onset of asecond said cardiovascular event of said subject compared with controlsubjects.
 16. The method of claim 14, wherein the subject has diabetesmellitus and the control subjects each have diabetes mellitus or thesubject has metabolic syndrome and the control subjects each havemetabolic syndrome.
 17. The method of claim 1, wherein theadministration further reduces the risk of stroke and/or risk ofmyocardial infarction.
 18. A method of reducing risk of a cardiovascularevent in a subject on statin therapy with residual atherogenicdyslipidemia and clinically evident cardiovascular disease, the methodcomprising administering to the subject about 2 g to about 4 g of apharmaceutical composition comprising eicosapentaenoic acid anddocosapentaenoic acid per day for a period of at least about 2 years,wherein said administration reduces risk of cardiovascular death, needfor coronary revascularization, risk of unstable angina, risk of strokeand/or risk of myocardial infarction.
 19. The method of claim 18,wherein the composition is administered to the subject in 1 to 4 dosageunits per day.
 20. The method of claim 18, wherein the eicosapentaenoicacid comprises at least about 90 wt. % of all omega-3 fatty acids in thepharmaceutical composition.
 21. The method of claim 18, wherein theeicosapentaenoic acid comprises at least about 96 wt. % of all omega-3fatty acids in the pharmaceutical composition.
 22. The method of claim18, wherein the docosapentaenoic acid comprises less than 10 wt. % ofall omega-3 fatty acids in the pharmaceutical composition.
 23. Themethod of claim 18, wherein the docosapentaenoic acid comprises lessthan 8 wt. % of all omega-3 fatty acids in the pharmaceuticalcomposition.
 24. The method of claim 18, wherein the docosapentaenoicacid comprises less than 5 wt. % of all omega-3 fatty acids in thepharmaceutical composition.
 25. The method of claim 18, wherein thepharmaceutical composition further comprises less than 5%docosahexaenoic acid, by weight, of all omega-3 fatty acids in thepharmaceutical composition.
 26. The method of claim 18 furthercomprising a step of measuring the subject's baseline lipid profileprior to administering the pharmaceutical composition to the subject.27. The method of claim 18, wherein the subject has one or more of: abaseline non-HDL-C value of about 200 mg/dL to about 300 mg/dL; abaseline total cholesterol value of about 250 mg/dL to about 300 mg/dL;a baseline VLDL-C value of about 140 mg/dL to about 200 mg/dL; abaseline HDL-C value of about 10 to about 30 mg/dL; and/or a baselineLDL-C value of about 40 to about 100 mg/dL.
 28. The method of claim 18,wherein the subject: (a) has not been administered 200 mg or more perday of niacin and/or fibrates for at least 28 days before administrationof the pharmaceutical composition; (b) has not been administered omega-3fatty acid prescription for a period of time beginning 28 days prior toadministration of the pharmaceutical composition; or (c) has notingested dietary supplements comprising omega-3 fatty acids for a periodof time beginning 28 days prior to administration of the pharmaceuticalcomposition.
 29. The method of claim 18, wherein the subject isadministered about 3 g or about 4 g of the pharmaceutical compositionper day for at least about 3 years.
 30. The method of claim 18, whereinthe pharmaceutical composition is formulated to delay onset of a firstsaid cardiovascular event of said subject compared with controlsubjects, wherein each said control subject is on stable statin therapy,has a fasting baseline triglyceride level of about 135 mg/dL to about500 mg/dL, and has established cardiovascular disease.